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PubMed1983

Echocardiographic assessment of left ventricular hypertrophy in patients with obstructive or nonobstructive hypertrophic cardiomyopathy.

In patients with hypertrophic cardiomyopathy, wide-angle two-dimensional echocardiography is capable of detecting diverse patterns of myocardial hypertrophy that are often more extensive than may be appreciated by M-Mode echocardiography alone. In the vast majority of patients with hypertrophic cardiomyopathy the distribution of left ventricular hypertrophy is 'asymmetric'. Left ventricular wall thickening commonly involves substantial portions of the ventricular septum and free wall but rarely extends into the posterior segment of free wall (through which the M-mode beam passes). Four basic patterns of distribution of left ventricular hypertrophy may be identified by two-dimensional echocardiography in patients with hypertrophic cardiomyopathy. Most frequently (52% of patients) hypertrophy involves both the ventricular septum and anterolateral free wall (Type III). In other patients, hypertrophy is confined to the anterior portion of ventricular septum (Type I), involves the entire septum but not the free wall (Type II), or is limited to regions of the left ventricular wall other than the basal anterior ventricular septum (Type IV)--i.e. posterior segment of septum, anterolateral free wall, or septum in its apical one-half (apical hypertrophic cardiomyopathy). In patients with morphologic Type IV, the sites of left ventricular hypertrophy are inaccessible to the path of the conventional M-mode beam and the diagnosis of hypertrophic cardiomyopathy can only be established with two-dimensional echocardiography. Patients with the most marked and widespread hypertrophy involving the septum and free wall (Type III) more frequently demonstrated moderate to severe functional limitation, the pattern of left ventricular hypertrophy on electrocardiogram, and subaortic obstruction at rest produced by systolic anterior motion of the mitral valve in the presence of a small left ventricular outflow tract.

Adolescent↗
PubMed1991

Left ventricular hypertrophy and skin color among American blacks.

The association between skin color, a measure of black-white genetic admixture, and left ventricular hypertrophy was examined in 551 black men and women, from three US cities, who underwent electrocardiography and skin reflectance measurements during 1972-1974. The overall prevalence of left ventricular hypertrophy (Minnesota Code 3-1 or 3-3) was 14% (18% in men; 11% in women). Left ventricular hypertrophy was strongly associated with systolic (p less than 0.001) and diastolic (p = 0.001) blood pressure, but less so with skin color (p = 0.09) [corrected]. The prevalence of left ventricular hypertrophy was 16% in the darkest versus 12% in the lightest quartile of skin color. In a multiple logistic regression model, adjusting for systolic blood pressure and blood pressure medication use, the relation between left ventricular hypertrophy and skin color was insignificant (p = 0.18); the odds ratio of having left ventricular hypertrophy in dark (75th percentile of skin color) versus light (25th percentile) skinned blacks after adjustment for systolic blood pressure, systolic blood pressure medications, age, and sex was 1.2 (95 percent confidence interval 0.8-1.8). Overall, the association between left ventricular hypertrophy and skin color was weak and not statistically significant, suggesting that black individuals do not have a genetic susceptibility to the effects of blood pressure on the myocardium. We did not postulate any significant effect modification of this association by sex. However, the data suggest that the association between skin color and left ventricular hypertrophy may be different between men and women.

Adult↗
PubMed1990

Effect of pinacidil on myocardial blood flow in the chronically pressure overloaded hypertrophied left ventricle.

This study examined the effect of pinacidil on the transmural distribution of myocardial blood flow in the chronically pressure overloaded hypertrophied left ventricle. Studies were performed in six dogs in which banding of the ascending aorta had resulted in an 88% increase in left ventricular mass, as well as in six normal control animals. Two doses of pinacidil were administered to decrease mean arterial pressure by approximately 10 mm Hg (low dose) and 20 mm Hg (high dose). Animals with hypertrophy required significantly smaller drug doses to achieve the desired reductions in arterial pressure. During control conditions mean myocardial blood flow was significantly higher in animals with hypertrophy (1.90 +/- 0.21 ml/min/g) than in normal animals (1.12 +/- 0.08 ml/min/g; p less than 0.05). Subendocardial flow (endo) exceeded subepicardial flow (epi) in normal dogs during control conditions (endo/epi = 1.41 +/- 0.13), but not in animals with hypertrophy (endo/epi = 1.06 +/- 0.06; p less than 0.05). Pinacidil caused coronary vasodilation with similar relative increases in blood flow in both normal and hypertrophied hearts, so that after pinacidil, absolute blood flow rates remained higher than normal in animals with hypertrophy. Pinacidil caused a redistribution of blood flow away from the subendocardium in normal hearts (endo/epi = 0.90 +/- 0.11 during high-dose pinacidil) and in hearts with hypertrophy (endo/epi = 0.81 +/- 0.13 during high-dose pinacidil). The endo/epi ratios during high-dose pinacidil were not significantly different between the two groups. This study demonstrates that pinacidil is a potent coronary vasodilator in both normal and hypertrophied hearts.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Losartan attenuates phospholipase C isozyme gene expression in hypertrophied hearts due to volume overload.

Because the left ventricular (LV) hypertrophy due to volume overload induced by arteriovenous (AV) shunt was associated with an increase in phospholipase C (PLC) isozyme mRNA levels, PLC is considered to be involved in the development of cardiac hypertrophy. Since the renin-angiotensin system (RAS) is activated in cardiac hypertrophy, the role of RAS in the stimulation of PLC isozyme gene expression in hypertrophied heart was investigated by inducing AV shunt in Sprague-Dawley rats. The animals were treated with or without losartan (20 mg/kg, daily) for 3 days as well as 1, 2 and 4 weeks, and atria, right ventricle (RV) and LV were used for analysis. The increased muscle mass as well as the mRNA levels for PLC beta1 and beta3 in atria and RV, unlike PLC beta3 gene expression in LV, at 3 days of AVshunt were attenuated by losartan. The increased gene expression for PLC beta1 at 2 weeks in atria, at 1 and 4 weeks in RV, and at 2 and 4 weeks in LV was also depressed by losartan treatment. Likewise, the elevated mRNA levels for PLC beta3 in RV at 1 week and in LVat 4 weeks of cardiac hypertrophy were decreased by losartan. On the other hand, the increased levels of mRNA for PLC gamma1 in RV and LV at 2 and 4 weeks of inducing hypertrophy, unlike in atria at 4 weeks were not attenuated by losartan treatment. While the increased mRNA level for PLC delta1 in LV was reduced by losartan, gene expression for PLC delta1 was unaltered in atria and decreased in RV at 3 days of inducing AV shunt. These results suggest that changes in PLC isozyme gene expression were chamber specific and time-dependent upon inducing cardiac hypertrophy due to AV shunt. Furthermore, partial attenuation of the increased gene expression for some of the PLC isozymes and no effect of losartan on others indicate that both RAS dependent and independent mechanisms may be involved in hypertrophied hearts due to volume overload.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2005

Trimetazidine normalizes postischemic function of hypertrophied rat hearts.

The fraction of glucose passing through glycolysis that is oxidized is low in hypertrophied hearts, a pattern of glucose use associated with poor postischemic contractile function. We tested the hypothesis that trimetazidine, a partial 3-ketoacyl coenzyme A thiolase inhibitor, would stimulate glucose oxidation and, thereby, improve fractional glucose oxidation and postischemic function of hypertrophied hearts. Function, glycolysis, and oxidation of glucose, lactate, and palmitate were measured before and after global no-flow ischemia in isolated working hearts from sham-operated (control) and aortic-constricted (hypertrophied) male Sprague-Dawley rats in the presence or absence of 1 microM trimetazidine. Heart function was significantly improved by trimetazidine after ischemia, but only in hypertrophied hearts, with function improving to values in untreated control hearts. This effect occurred in association with relatively minor changes in oxidative metabolism. However, trimetazidine reduced glycolysis by approximately 30% but did so only in hypertrophied hearts, an unexpected novel action of this agent that resulted in a larger fractional oxidation of glucose, effectively normalizing it in hypertrophied hearts. Thus, trimetazidine normalizes postischemic function and fractional glucose oxidation in hypertrophied hearts, mainly by reducing glycolysis. These data extend the potential usefulness of trimetazidine and provide support for its use as a means to improve postischemic function of pressure overload hypertrophied hearts.

Adenosine Triphosphate↗
PubMed2006

Calcineurin activation is not necessary for Doxorubicin-induced hypertrophy in H9c2 embryonic rat cardiac cells: involvement of the phosphoinositide 3-kinase-Akt pathway.

The calcium/calmodulin-dependent phosphatase calcineurin has been shown to be both necessary and sufficient to induce cardiac hypertrophy in vivo and in vitro. Treatment with the antineoplastic agent doxorubicin (DOX) was shown to activate calcineurin signaling in H9c2 rat cardiac muscle cells; however, the effect of this activation on hypertrophy was not investigated. Therefore, the present study was undertaken to examine the involvement of calcineurin activation in DOX-induced cardiac cell hypertrophy. H9c2 cells were treated with 1 microM DOX for 2 h following pretreatment with and in the presence of calcineurin inhibitors cyclosporine A (CsA) or FK506 (tacrolimus). Subsequent analysis of calcineurin signaling and cellular hypertrophy was performed 8 to 48 h after the treatment. DOX treatment activated calcineurin signaling and resulted in cellular hypertrophy as assessed by an increase in cell volume and protein content per cell. Inhibition of calcineurin with CsA or FK506 blocked DOX-induced calcineurin signaling. However, this inhibition did not prevent the DOX-induced hypertrophic response in H9c2 cells. Further evaluation of the possible signaling pathways involved in DOX-induced H9c2 cellular hypertrophy revealed that DOX treatment resulted in phosphorylation of the serine/threonine protein kinase Akt, a downstream effector of phosphoinositide 3-kinase (PI3K). Moreover, the DOX-induced hypertrophic response was blunted by LY294002 [2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one], a specific inhibitor for PI3K. These results demonstrate that, although calcineurin is activated by DOX treatment, it is not necessary for DOX-induced hypertrophy in H9c2 cells. Rather, the PI3K-Akt signaling pathway seems to be more critically involved in DOX-induced hypertrophy.

Animals↗
PubMed1971

Ventricular hypertrophy in cardiomyopathy.

Semantic difficulties arise when hypertrophic obstructive cardiomyopathy is seen without obstruction and with congestive failure, and also when congestive cardiomyopathy is seen with gross hypertrophy but without heart failure. Retention of a small left ventricular cavity and a normal ejection fraction characterizes hypertrophic cardiomyopathy at all stages of the disorder. Congestive cardiomyopathy is recognized by the presence of a dilated left ventricular cavity and reduced ejection fraction regardless of the amount of hypertrophy and the presence or not of heart failure. Longevity in congestive cardiomyopathy seems to be promoted when hypertrophy is great relative to the amount of pump failure as measured by increase in cavity size. Conversely, death in hypertrophic cardiomyopathy is most likely when hypertrophy is greatest at a time when outflow tract obstruction has been replaced by inflow restriction caused by diminishing ventricular distensibility. Hypertrophy is thus beneficial and compensatory in congestive cardiomyopathy, whereas it may be the primary disorder and eventual cause of death in hypertrophic cardiomyopathy. Reasons are given for believing that hypertension may have been the original cause of left ventricular dilatation in some case of congestive cardiomyopathy in which loss of stroke output thenceforward is followed by normotension. Development of severe hypertension in these patients after recovery from a prolonged period of left ventricular failure with normotension lends weight to this hypothesis. No fault has been found in the large or small coronary arteries in either hypertrophic cardiomyopathy or congestive cardiomyopathy when they have been examined in life by selective coronary angiography, or by histological methods in biopsy or post-mortem material. Coronary blood supply may be a limiting factor in the compensatory hypertrophy of congestive cardiomyopathy, and the ability to hypertrophy may explain the better prognosis of some patients. In hypertrophic cardiomyopathy excessive metabolic demand may not be met, and inadequacy of blood flow may contribute both to sudden death and to progressive replacement fibrosis in this disease. Histochemical and ultrastructural methods have failed to show any fundamental differences between hypertrophic cardiomyopathy and congestive cardiomyopathy, whereas conventional histology permits recognition of hypertrophic cardiomyopathy and distinction both from congestive cardiomyopathy and from ;normal' secondary hypertrophy in organic aortic stenosis.

Angiocardiography↗
PubMed1992

Variable patterns of ST-T abnormalities in patients with left ventricular hypertrophy and normal coronary arteries.

BACKGROUND: Classically, the ST-T configuration in the electrocardiogram of patients with left ventricular hypertrophy is said to have a typical pattern of ST depression together with asymmetrical T wave inversion (the so-called left ventricular strain pattern). However, many patients with left ventricular hypertrophy may also have ischaemic heart disease. To revise the electrocardiographic criteria for left ventricular hypertrophy the ST-T configuration in patients with left ventricular hypertrophy documented by echocardiography and with normal coronary arteries was assessed. METHODS: 24 patients were selected for this study. All had left ventricular hypertrophy documented by echocardiography, normal coronary arteries by cardiac catheterisation, and ST and/or T wave abnormalities in the lateral leads of their electrocardiogram. There were eight patients with aortic valve disease and 16 with hypertension who had coronary angiography as part of an investigation into the risk factors of sudden cardiac death caused by hypertensive left ventricular hypertrophy. No patient was receiving digitalis preparations or had electrolyte disturbances, and none had a previous myocardial infarction or ventricular conduction defect. RESULTS: Typical electrocardiographic evidence of left ventricular strain was found in approximately two thirds (63%) of patients and 95% of this subgroup had asymmetrical T wave inversion. Flat ST segment depression, with or without T wave inversion or isolated T wave inversion (symmetrical or asymmetrical) in the anterolateral leads, was seen in the remaining 37% of patients. CONCLUSIONS: These findings indicate that left ventricular hypertrophy without coronary artery disease can cause variable types of ST-T abnormalities in the anterolateral leads including the typical left ventricular strain pattern and non-specific ST-T changes. Non-specific abnormalities could not be distinguished from those of coronary artery disease and may adversely affect the accuracy of the electrocardiographic criteria for the diagnosis of left ventricular hypertrophy because they do not accord with the criteria for left ventricular strain.

Adult↗
PubMed2004

Alterations in apoptosis regulatory factors during hypertrophy and heart failure.

Cardiac hypertrophy from pathological stimuli often proceeds to heart failure, whereas cardiac hypertrophy from physiological stimuli does not. In this study, physiological hypertrophy was created by a daily exercise regimen and pathological hypertrophy was created from a high-salt diet in Dahl salt-sensitive rats. The rats continued on a high-salt diet progressed to heart failure associated with an increased rate of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cardiomyocytes. We analyzed primary cultures of these hearts and found that only cardiomyocytes made hypertrophic by a pathological stimulus show increased sensitivity to apoptosis. Examination of the molecular changes associated with these distinct types of hypertrophy revealed changes in Bcl-2 family members and caspases favoring survival during physiological hypertrophy. However, in pathological hypertrophy, there were more diffuse proapoptotic changes, including changes in Fas, the Bcl-2 protein family, and caspases. Therefore, we speculate that this increased sensitivity to apoptotic stimulation along with proapoptotic changes in the apoptosis program may contribute to the development of heart failure seen in pathological cardiac hypertrophy.

Animals↗
PubMed1982

Passive electrical properties of normal and hypertrophied rat myocardium.

We determined the electrical constants of epicardial and endocardial preparations from both normal and hypertrophied rat hearts. This was done by comparative analysis of the spatial decay of steady-state electronic voltage deflection produced by injection of a hyperpolarizing constant-current pulse. We used a two-dimensional finite disk model to obtain the apparent membrane resistance, (Rm)app, and internal longitudinal resistivity (Ri), (Rm)app was significantly larger in epicardial (565 +/- 222 omega . cm2) than endocardial (375 +/- 137) preparations from normal hearts. This regional difference disappeared in hypertrophied hearts (epicardium 421 +/- 138, endocardium 383 +/- 121 omega . cm2). Ri was similar for normal endocardial (272 +/- 169 omega . cm) and epicardial (326 +/- 152) preparations, as well as for hypertrophied endocardial (251 +/- 108) and epicardial (312 +/- 59) preparations. We determined the effective membrane capacity (Ceff) by measuring the ratio of applied charge to the displacement of membrane potential. Ceff was larger for normal hearts (epicardium 9.7 +/- 2.5 micro F/cm2, endocardium 7.5 +/- 3.0) than for hypertrophied hearts (epicardium 4.1 +/- 1.4, endocardium 4.7 +/- 1.2). From the values for Ceff we calculated the effective membrane resistance, (Rm)eff. (Rm)eff was larger for normal (epicardium 5,392 +/- 2,613 omega . cm2, endocardium 3,013 +/- 2,096) than for hypertrophied (epicardium 1,552 +/- 633, endocardium 1,838 +/- 826) preparations. Our results show that the amount of electrically effective membrane area is decreased in hypertrophied myocardium, despite the increased total area per hypertrophied cell. One functional implication of this finding is that activation of contraction by spread of surface electrical depolarization into the T-tubules may be impaired in hypertrophied cardiac muscle.

Animals↗
PubMed1985

Decreased auxotonic sarcomere shortening in hypertrophied rabbit myocardium.

Auxotonic sarcomere length change occurs during isometric twitches of isolated cardiac muscle preparations. To assess the amount of internal work in hypertrophied myocardium, we measured auxotonic sarcomere length change during isometric tension development over a range of initial muscle and sarcomere lengths. Hypertrophy was produced by banding the pulmonary artery, which resulted in an increase in the ratio of right ventricular free wall weight to total ventricular weight (normal 0.19 +/- 0.004; hypertrophy 0.35 +/- 0.008; P less than 0.001). Right ventricular free wall trabeculae and papillary muscles were studied with optical and mechanical instrumentation, including a helium-neon laser, to measure sarcomere length and isometric twitch parameters. The resting sarcomere length-resting tension relationship was shifted to the left of normal in the hypertrophied preparations (P less than 0.001). The relationship of sarcomere length at the peak of the twitch with total tension at the same instant was shifted downward and to the right of normal in hypertrophy (P less than 0.01). For the same amount of total tension development there was less than normal sarcomere shortening in the hypertrophied preparations (P less than 0.001). Consequently, there is less than normal work per sarcomere during auxotonic sarcomere shortening in hypertrophied heart muscle. Less sarcomere work for a particular functional state is important to consider in the assessment of the basis of myocardial function in compensated pressure overload hypertrophy.

Adaptation, Physiological↗
PubMed1986

Cardiac vasculature and flow during pressure-overload hypertrophy.

The effects of pressure-overload hypertrophy (H) on myocardial blood flow and microvasculature were studied in the porcine left ventricle. Hypertrophy was produced in nine adult pigs by an aortic cuff constriction of the ascending aorta. Eight pigs served as controls. After 30 days the aortic cuff was released, and the hypertrophy group was studied 1 day postrelease. The degree of hypertrophy, determined by left ventricular-to-body weight ratio, was 45%. With hypertrophy, left ventricular blood flows were normal at rest. During exercise with adenosine infusion, myocardial blood flow to the endomyocardium was reduced compared with the control (C) group (H = 4.02 +/- 0.35, P less than 0.05; C = 5.33 +/- 0.41 ml X min-1 X g-1). Minimal coronary vascular resistance in the endomyocardium was increased during exercise with adenosine in the hypertrophy group compared with the control group. Anatomic studies revealed that hypertrophy causes a reduction in the endomyocardial capillary density (H = 1,654 +/- 168, P less than 0.025; C = 2,168 +/- 106, no./mm2) with a similar trend noted for the transmural arteriolar density. Arteriolar media wall cross-sectional area was unaffected by the pressure overload. These results indicate that changes in the vascular bed do not parallel myocyte growth during pressure-overload hypertrophy. The resultant anatomic imbalance compromises endomyocardial flow, making this region vulnerable to ischemia.

Animals↗
PubMed1993

Collagen characterization in volume-overload- and pressure-overload-induced cardiac hypertrophy in minipigs.

Previous studies in several different species have shown reduced extractability of collagens in some types of cardiac hypertrophy (volume overload) but not others (pressure overload). The objective of the present study was to examine collagen proteins from the same species (minipigs) with both pressure-overload- and volume-overload-induced cardiac hypertrophy. Hypertrophy was induced by two methods: thoracic banding of the aorta to create pressure overload and arteriovenous shunt to cause volume overload in a porcine model. Collagen types I, III, IV, and V were isolated by pepsin digestion from normal and hypertrophied pig left ventricle tissues. Types I and III collagens from normal and hypertrophied samples, when separated from types IV and V, were digested with cyanogen bromide (CB), and the peptides were examined. Collagen concentration was increased in myocardium removed from hearts subjected to volume overload and unchanged in hearts subjected to pressure overload. The extractability of total collagen was unaffected in pressure-overloaded left ventricles but lower in samples from volume-overloaded hearts. CB digestion cleaved all of the types I and III collagens into similar smaller CB peptides with the exception of a 100-kDa peptide that was observed in both control and hypertrophied hearts. This peptide corresponds to one of the high-molecular-weight peptides found in canine heart tissue. The mature collagen cross-link hydroxylysylpyridinoline (HP) was identified in normal and hypertrophied types I and III collagen from porcine sources. Pressure-overload- and volume-overload-induced cardiac hypertrophy in the pig produced different alterations in the extracellular matrix.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗
PubMed2001

Bioenergetics in cardiac hypertrophy: mitochondrial respiration as a pathological target of NO*.

A rat aortic banding model of cardiac hypertrophy was used to test the hypothesis that reversible inhibition of mitochondrial respiration by nitric oxide (NO*) elicits a bioenergetic defect in the hypertrophied heart. In support of this hypothesis, the respiration of myocytes isolated from hypertrophied hearts was more sensitive to exogenous NO* (IC(50) 200 +/- 10 nM vs. 290 +/- 30 nM in controls, P = 0.0064). Hypertrophied myocytes also exhibited significantly elevated inducible NO* synthase (iNOS). Consistent with this endogenous source for NO*, the respiration of hypertrophied myocytes was significantly inhibited at physiological O(2) tensions versus controls. Both the nonspecific NOS inhibitor nitro-L-arginine and the iNOS-specific inhibitor N-[3-(aminomethyl)- benzyl]acetamidine. 2HCl reversed this inhibition, with no effect on respiration of control myocytes. Consistent with an NO*-mediated mitochondrial dysfunction, the ability of intact perfused hearts to respond to a pacing workload was impaired in hypertrophy, and this effect was reversed by NOS inhibition. We conclude that endogenously generated NO* can modulate mitochondrial function in the hypertrophied heart and suggest that this bioenergetic defect may underlie certain pathological features of hypertrophy.

Amidines↗
PubMed2001

Physiological and pathological cardiac hypertrophy induce different molecular phenotypes in the rat.

Pressure overload, such as hypertension, to the heart causes pathological cardiac hypertrophy, whereas chronic exercise causes physiological cardiac hypertrophy, which is defined as athletic heart. There are differences in cardiac properties between these two types of hypertrophy. We investigated whether mRNA expression of various cardiovascular regulating factors differs in rat hearts that are physiologically and pathologically hypertrophied, because we hypothesized that these two types of cardiac hypertrophy induce different molecular phenotypes. We used the spontaneously hypertensive rat (SHR group; 19 wk old) as a model of pathological hypertrophy and swim-trained rats (trained group; 19 wk old, swim training for 15 wk) as a model of physiological hypertrophy. We also used sedentary Wistar-Kyoto rats as the control group (19 wk old). Left ventricular mass index for body weight was significantly higher in SHR and trained groups than in the control group. Expression of brain natriuretic peptide, angiotensin-converting enzyme, and endothelin-1 mRNA in the heart was significantly higher in the SHR group than in control and trained groups. Expression of adrenomedullin mRNA in the heart was significantly lower in the trained group than in control and SHR groups. Expression of beta(1)-adrenergic receptor mRNA in the heart was significantly higher in SHR and trained groups than in the control group. Expression of beta(1)-adrenergic receptor kinase mRNA, which inhibits beta(1)-adrenergic receptor activity, in the heart was markedly higher in the SHR group than in control and trained groups. We demonstrated for the first time that the manner of mRNA expression of various cardiovascular regulating factors in the heart differs between physiological and pathological cardiac hypertrophy.

Actins↗
PubMed2006

Differential role of rho-kinase in pathological and physiological cardiac hypertrophy in rats.

The present study was undertaken to investigate the effect of fasudil, a specific Rho-kinase inhibitor, in pathological cardiac hypertrophy induced by partial abdominal aortic constriction (PAAC) for 4 weeks in comparison with physiological cardiac hypertrophy caused by chronic swimming training (CST) for 8 weeks in rats. Fasudil (15 and 30 mg/kg day(-1) p.o.) treatment was started 3 days before PAAC and CST, and was continued for 4 weeks in PAAC and 8 weeks in the CST experimental model. Left ventricular (LV) function and LV hypertrophy were assessed by measuring LVDP, +dp/dt(max), -dp/dt(max), ratio of LV weight to body weight (LVW/BW), LV wall thickness (LVWT), LV collagen content, protein content and RNA concentration. Further, venous pressure (VP) and mean arterial blood pressure (MABP) were recorded. Moreover, DNA gel electrophoresis was employed to assess myocardial cell death. PAAC but not CST produced LV dysfunction by decreasing LVDP, +dp/dt(max), -dp/dt(max) and increasing LV collagen content. Further, PAAC and CST were noted to produce LV hypertrophy by increasing LVW/BW, LVWT, LV protein content and LV RNA concentration. Moreover, in contrast to CST, PAAC has significantly increased VP, MABP and LV necrotic cell death. Fasudil, a Rho-kinase inhibitor, markedly attenuated PAAC-induced LV dysfunction, LV hypertrophy, increase in VP, MABP and LV necrotic cell death. However, it did not modulate the CST-induced LV hypertrophy. These results have implicated Rho-kinase in PAAC-induced LV dysfunction and pathological cardiac hypertrophy. However, Rho-kinase may not be involved in CST-induced physiological cardiac hypertrophy.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed2002

Calcineurin in human heart hypertrophy.

BACKGROUND: In animal models, increased signaling through the calcineurin pathway has been shown to be sufficient for the development of cardiac hypertrophy. Calcineurin activity has been reported to be elevated in the myocardium of patients with congestive heart failure. In contrast, few data are available about calcineurin activity in patients with pressure overload or cardiomyopathic hypertrophy who are not in cardiac failure. METHODS AND RESULTS: We investigated calcineurin activity and protein expression in 2 different forms of cardiac hypertrophy: hypertrophic obstructive cardiomyopathy (HOCM) and aortic stenosis (AS). We found that the C-terminus of calcineurin A protein containing the autoinhibitory domain was less abundant in myocardial hypertrophy than in normal heart, which suggests the possibility of proteolysis. No new splice variants could be detected by reverse-transcription polymerase chain reaction. This resulted in a significant elevation of calcineurin enzymatic activity in HOCM and AS compared with 6 normal hearts. Increased calcineurin phosphatase activity caused increased migration of NF-AT2 (nuclear factor of activated T cells 2) in SDS-PAGE compatible with pronounced NF-AT dephosphorylation in hypertrophied myocardial tissue. CONCLUSIONS: Hypertrophy in HOCM and AS without heart failure is characterized by a significant increase in calcineurin activity. This might occur by (partial) proteolysis of the calcineurin A C-terminus containing the autoinhibitory domain. Increased calcineurin activity has functional relevance, as shown by altered NF-AT phosphorylation state. Although hypertrophy in AS and HOCM may be initiated by different upstream triggers (internal versus external fiber overload), in both cases, there is activation of calcineurin, which suggests an involvement of this pathway in the pathogenesis of human cardiac hypertrophy.

Aortic Valve Stenosis↗
PubMed1999

Calcineurin plays a critical role in pressure overload-induced cardiac hypertrophy.

BACKGROUND: Cardiac hypertrophy is a fundamental adaptive response to hemodynamic overload; how mechanical load induces cardiac hypertrophy, however, remains elusive. It was recently reported that activation of a calcium-dependent phosphatase, calcineurin, induces cardiac hypertrophy. In the present study, we examined whether calcineurin plays a critical role in pressure overload-induced cardiac hypertrophy. METHODS AND RESULTS: Pressure overload produced by constriction of the abdominal aorta increased the activity of calcineurin in the rat heart and induced cardiac hypertrophy, including reprogramming of gene expression. Treatment of rats with a calcineurin inhibitor, FK506, inhibited the activation of calcineurin and prevented the pressure overload-induced cardiac hypertrophy and fibrosis without change of hemodynamic parameters. Load-induced expression of immediate-early-response genes and fetal genes was also suppressed by the FK506 treatment. CONCLUSIONS: The present results suggest that the calcineurin signaling pathway plays a pivotal role in load-induced cardiac hypertrophy and may pave the way for a novel pharmacological approach to prevent cardiac hypertrophy.

Animals↗