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PubMed1992

Collagen deposition and the reversal of coronary reserve in cardiac hypertrophy.

The aim of this study was to clarify how collagen deposition or medial hypertrophy of the vascular wall affects the coronary dilator reserve in pressure-overloaded hearts and whether inhibition of collagen deposition reverses the abnormalities after relief of pressure overload. We used ascending aortic banding and debanding methods and superimposed beta-aminopropionitrile in some of the banded rats (50 mg/kg i.p., twice a day). Ten weeks of banding increased in vivo peak systolic left ventricular pressure and produced medial hypertrophy, an increase in collagen deposition in the myocardial and perivascular tissues, and myocardial hypertrophy in the banded group without beta-aminopropionitrile treatment. Superimposition of beta-aminopropionitrile treatment on banding inhibited the increase in collagen deposition. In the groups debanded after the 10-week banding period, both with and without beta-amino-propionitrile treatment, medial and myocardial hypertrophy regressed 4 weeks after debanding. We estimated coronary dilator reserve in Langendorff preparations perfused with modified Tyrode's solution containing oxygenated bovine red blood cells and serum albumin. The ratio of reactive peak flow after brief ischemia-to-resting flow decreased in both of the banded groups. After debanding, the ratio remained lower in the banded group without beta-aminopropionitrile treatment than in the control group. However, debanding in the group with beta-aminopropionitrile treatment increased the ratio to a level similar to that of the control group. Thus, in pressure-overloaded cardiac hypertrophy with coronary hypertension, coronary reserve seems to be determined by medial hypertrophy independently of collagen deposition, but collagen deposition plays an important role in the reversal of vasodilator reserve after relief of the overload.

Aminopropionitrile↗
PubMed2003

Apoptosis signal-regulating kinase 1 plays a pivotal role in angiotensin II-induced cardiac hypertrophy and remodeling.

Multiple lines of evidence establish that angiotensin II (Ang II) induces not only hypertension but also directly contributes to cardiac diseases. Apoptosis signal-regulating kinase 1 (ASK1), one of mitogen-activated protein kinase kinase kinases, plays a key role in stress-induced cellular responses. However, nothing is known about the role of ASK1 in cardiac hypertrophy and remodeling in vivo. In this study, by using mice deficient in ASK1 (ASK1-/- mice), we investigated the role of ASK1 in cardiac hypertrophy and remodeling induced by Ang II. Left ventricular (LV) ASK1 was activated by Ang II infusion in wild-type mice, which was mediated by angiotensin II type 1 receptor and superoxide. Although Ang II-induced hypertensive effect was comparable to wild-type and ASK1-/- mice, LV ASK1 activation by Ang II was not detectable in ASK1-/- mice, and p38 and c-Jun N-terminal kinase (JNK) activation was lesser in ASK-/- mice than in wild-type mice. Elevation of blood pressure by continuous Ang II infusion was comparable between ASK1-/- and wild-type mice. However, Ang II-induced cardiac hypertrophy and remodeling, including cardiomyocyte hypertrophy, cardiac hypertrophy-related mRNA upregulation, cardiomyocyte apoptosis, interstitial fibrosis, coronary arterial remodeling, and collagen gene upregulation, was significantly attenuated in ASK1-/- mice compared with wild-type mice. These results provided the first in vivo evidence that ASK1 is the critical signaling molecule for Ang II-induced cardiac hypertrophy and remodeling. Thus, ASK1 is proposed to be a potential therapeutic target for cardiac diseases.

Angiotensin II↗
PubMed2005

Glycogen synthase kinase 3beta inhibits myocardin-dependent transcription and hypertrophy induction through site-specific phosphorylation.

Cardiomyocyte hypertrophy is transcriptionally controlled and inhibited by glycogen synthase kinase 3beta (GSK3beta). Myocardin is a muscle-specific transcription factor with yet unknown relation to hypertrophy. Therefore, we investigated whether myocardin is sufficient to induce cardiomyocyte hypertrophy and whether myocardin is regulated by GSK3beta through site-specific phosphorylation. Adenoviral myocardin overexpression induced cardiomyocyte hypertrophy in neonatal rat cardiomyocytes, with increased cell size, total protein amount, and transcription of atrial natriuretic factor (ANF). In vitro and in vivo (HEK 293 cells) kinase assays with synthetic peptides and full-length myocardin demonstrated that myocardin was a "primed" GSK3beta substrate, with serines 455 to 467 and 624 to 636 being the major GSK3beta phosphorylation sites. Myocardin-induced ANF transcription and increase in total protein amount were enhanced by GSK3beta blockade (10 mmol/L LiCl), indicating that GSK3beta inhibits myocardin. A GSK3beta phosphorylation-resistant myocardin mutant (8xA) activated ANF transcription twice as potently as wildtype myocardin under basal conditions with GSK3beta being active. Conversely, a GSK3beta phospho-mimetic myocardin mutant (8xD) was transcriptionally repressed after GSK3beta blockade, indicating that GSK3beta phosphorylation at the sites identified inhibits myocardin transcriptional activity. GAL4-myocardin fusion constructs demonstrated that GSK3beta phosphorylation reduced the intrinsic myocardin transcriptional activity. A cell-permeable (Antennapedia protein transduction tag) peptide containing the mapped myocardin GSK3beta motifs 624 to 636 induced hypertrophy of cultured cardiomyocytes, suggesting that the peptide acted as substrate-based GSK3beta inhibitor in cardiomyocytes. Therefore, we conclude that the GSK3beta-myocardin interaction constitutes a novel molecular control of cardiomyocyte hypertrophy. Phosphorylation by GSK3beta comprises a novel post-transcriptional regulatory mechanism of myocardin.

Animals↗
PubMed1977

Intercapillary distance and capillary reserve in hypertrophied rat hearts beating in situ.

Functional intercapillary distance (ICD) was measured in stop-motion photomicrographs of hypertrophied, normally compensated, well oxygenated rat hearts beating in situ. Left ventricular hypertrophy was produced by salt loading and unilateral nephrectomy. Minimum ICD (when all capillaries are open) also was measured. Ventricular weight increased by 30-40% within 8-9 weeks after nephrectomy. To compare the effect of normal and pathological growth, ICD was also measured in normal rats. In normal animals, minimum ICD and functional ICD increased linearly and proportionately with left ventricular weight. Consequently, the extent to which capillary recruitment could decrease ICD was the same in large and small normal hearts (about 2 micrometer). In the hypertrophied hearts, capillary recruitment could have maintained ICD within normal limits at rest for several weeks. After 8-9 weeks, however, the capillary reserve in hypertrophy was fully utilized at rest, and mean functional ICD was 1.5-2.0 micrometer greater than normal for the age of the animal. An analysis of O2 transport indicates that anoxic foci would exist throughout the hypertrophied heart and particularly in subendocardium when the capillary reserve is exhausted. The calculated amount of anoxic tissue appears sufficient to account for the focal necrosis and fibrosis observed in hypertrophy and for the development of circulatory failure.

Animals↗
PubMed1981

Passive stiffness of pressure-induced hypertrophied cat myocardium.

The effect of myocardial hypertrophy on passive stiffness was determined from the stress (sigma)-strain relationship of right ventricular papillary muscles from 18 pulmonary artery-banded and 21 non-banded cats. By use of Lagrangian strain, (1-lo)lo is initial muscle length, and instantaneous stress elastic constants beta and alpha were calculated from the equation sigma = alpha(ebeta epsilon - 1). Elastic stiffness (d sigma/d epsilon) was determined from the formula d sigma/d epsilon = beta alpha + alpha beta. Banding produced an average increase in RV mass of 70%. Beta averaged 14.2 +/- 0.9 (SEM) and 16.0 +/- 0.8 in the non-hypertrophied and hypertrophied muscles, respectively (NS). However, elastic stiffness was significantly greater in hypertrophied muscles over the entire stress range. Contractile function varied widely among hypertrophied muscles but was not related to changes in stiffness. Thus, moderate degrees of pressure-induced hypertrophy are associated with a modest increase in the passive stiffness properties of the muscle, independent of changes in contractile function.

Animals↗
PubMed1982

Effects of duration and severity of arterial hypertension and cardiac hypertrophy on coronary vasodilator reserve.

Cardiac hypertrophy is associated with a decrease in coronary reserve. However, factors which may modulate the interaction between myocardial growth and vascular proliferation, such as duration and severity of hypertrophy, have not been evaluated. We measured myocardial perfusion with microspheres in conscious, chronically instrumented. Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats at 3, 7, and 15 months of age; and in SHR stroke-prone (SHR-SP) rats at 13-14 months of age. Myocardial perfusion was measured with microspheres in awake rats at rest and during maximal coronary dilation produced by dipyridamole infusion (2.0 mg/kg per min, iv). Arterial pressure was significantly elevated (P less than or equal to 0.05) in all hypertensive groups (vs. age-matched WKY), both at rest and during dipyridamole infusion. Left ventricular mass in the SHR rats was increased significantly (P less than or equal to 0.05) by 14%, 28%, and 29% at 3, 7, and 15 months, respectively. Left ventricular mass in the SHR-SP group was increased by 50% (P less than or equal to 0.05) compared to the 15-month-old WKY. Left ventricular minimal coronary vascular resistance (per gram) was significantly greater (P less than or equal to 0.05) in SHR at 7 months, and in the SHR-SP group (66% and 60%, respectively). Right ventricular minimal coronary vascular resistance was significantly greater (P less than or equal to 0.05) in SHR at 7 and 15 months (50%), and in the SHR-SP group (122%), compared to 15-month-old WKY. The results indicate the following: (1) the increase in minimal coronary vascular resistance between SHR and WKY rats was greatest when left ventricular hypertrophy peaked (7 months) and was no longer present after left ventricular hypertrophy had stabilized. (2) In 14-month-old SHR-SP rats, with more severe left ventricular hypertrophy and hypertension, minimal coronary vascular resistance was considerably higher than in SHR of approximately the same age. (3) Long-term arterial hypertension was associated with a higher right ventricular minimal coronary vascular resistance. Resistance appeared to change in proportion to the severity of hypertension, and the changes were independent of the presence of right ventricular hypertrophy.

Animals↗
PubMed1983

Contractile function, myosin ATPase activity and isozymes in the hypertrophied pig left ventricle after a chronic progressive pressure overload.

Experimental right ventricular pressure-overload hypertrophy in small mammals is associated with early muscle dysfunction, even before the onset of overt pump failure. Experimental results are quite heterogeneous regarding muscle function of the pressure hypertrophied left ventricle. Muscle dysfunction of the right or left ventricle, when found, may be causally related to alterations of myosin ATPase activity and isozyme type. However, the effect of a gradual pressure overload, analogous to that which occurs in human aortic stenosis, on myocardial contractile function and myosin ATPase activity has not been studied in a large animal whose normal myosin isozyme pattern resembles that of man. We therefore studied pump performance, myocardial contractile function, and myosin ATPase activity and isozyme pattern in pigs with severe, gradually applied left ventricular pressure overload. Thirteen weeks after supravalvular aortic banding, 10 pigs grew more than 7-fold in body weight and were found to have an aortic stenosis area of 0.5 +/- 0.1 cm2 with a gradient of 93 +/- 12 mm Hg. Compared with nine control animals, the banded animals had a 67% increase in left ventricular mass relative to body weight without overt pump failure as measured by cardiac index and pulmonary artery wedge pressure. Left ventricular ejection performance, measured as shortening fraction, was maintained except in three animals with extreme hypertrophy, in which depressed ejection performance may have been due to an afterload mismatch, myocardial dysfunction, or both. Myocardial contractile function, determined from the end-systolic stress-diameter relationship, was normal except in two pigs in which ejection performance was depressed and left ventricular mass was more than doubled. Only the slow V3 isozyme of myosin ATPase was found in both normal and hypertrophied pig myocardium, and the ATPase activity was normal in pigs with all degrees of hypertrophy. Thus, in a large animal model of severe, gradual left ventricular pressure overload, in which myosin isozyme pattern remains apparently unaltered, moderate hypertrophy can be associated with normal myosin ATPase activity and contractile function that is normal by current methods of evaluation.

Adenosine Triphosphatases↗
PubMed1987

Microtubules and desmin filaments during onset of heart hypertrophy in rat: a double immunoelectron microscope study.

The distribution of tubulin and desmin, the constituent proteins of microtubules and intermediate filaments, respectively, were studied in normal and hypertrophied rat myocardium by high-resolution immunofluorescence and immunoelectron microscopy. Cardiac hypertrophy was induced in 25-day-old rats by aortic stenosis. In the normal heart, double immunolabelling of ultrathin frozen sections of papillary muscle using gold-labelled probes for tubulin and desmin showed that microtubules ran primarily in a longitudinal direction through the intermyofibrillar spaces, perpendicularly to the desmin filaments. Microtubules were present near nuclei, mitochondria, and plasma membranes, while desmin filaments formed transverse connections between adjacent Z disks. No tubulin was observed near the intercalated disks, which were rich in desmin filaments. In hypertrophied hearts, myocytes exhibited the typical morphological features of developing hypertrophy. While there was little difference in the distribution of the microtubules around mitochondria and at the plasma membrane, considerable increases were seen near the nuclei and along the myofibrils. Desmin labelling was distributed transversely as in the controls; however, sometimes it was longitudinally oriented either in the intermyofibrillar space linking 2 Z disks out of register or along digitations of the intercalated disks connecting neighboring desmosomes. The unique rearrangement of desmin and tubulin filaments in hypertrophied cardiac myocytes emphasizes their distinct role in myocyte organization. We suggest that, during the development of cardiac hypertrophy, desmin filaments are mainly involved in maintaining the myofibrils in register, whereas the degree of assembly of microtubules is correlated with the rate of protein synthesis and with myofibrillogenesis.

Animals↗
PubMed1989

Fibrillar collagen and myocardial stiffness in the intact hypertrophied rat left ventricle.

This study tested the hypothesis that with hypertrophy, the proportion, distribution, and structural alignment of fibrillar collagen are important determinants of myocardial stiffness. Toward this end, the collagen volume fraction (morphometry), the transmural or subendocardial distribution of collagen, and the structural arrangement of fibrillar collagens (picrosirius red) were examined in the hypertrophied ventricle secondary to pressure overload (abdominal aorta banding or perinephritis), isoproterenol, and pressure overload plus isoproterenol. In the same hearts, the slopes of the systolic and diastolic stress-strain relations of the left ventricle, representing its active and passive stiffness, respectively, were obtained. In comparison with controls, we found 1) for a moderate rise in transmural collagen, active and passive stiffness increased with pressure-overload hypertrophy; 2) following isoproterenol alone there was a marked increase in subendocardial collagen, and active and passive stiffness increased; 3) in pressure-overload hypertrophy plus isoproterenol, active stiffness declined. Passive stiffness was increased except when fibrosis and thinning of the interventricular septum occurred, in which case it decreased; and 4) fibrillar collagens involved in remodeling included the formation of either collagen strands and fibers in a greater number of previously collagen-free intermuscular spaces in pressure-overload hypertrophy, or a dense crisscrossing latticework of fibers that encircled muscle fibers after isoproterenol. Thus, an increase in fibrillar collagen in pressure-overload hypertrophy is partially adaptive in that it enhances the tensile strength and three-dimensional delivery of force by the myocardium, but at the expense of reducing distensibility. The appearance of a dense collagen meshwork within the subendocardium after isoproterenol can be considered pathological in that it entraps muscle fibers causing active stiffness to fall while impairing distensibility. Finally, fibrosis may paradoxically reduce passive stiffness if it leads to a thinning of the interventricular septum.

Animals↗
PubMed1991

Altered calcium handling in left ventricular pressure-overload hypertrophy as detected with aequorin in the isolated, perfused ferret heart.

The purpose of this study was to test the hypothesis that systolic and diastolic dysfunction in left ventricular pressure-overload hypertrophy is caused by abnormal intracellular calcium handling. Experiments were performed with intact, buffer-perfused, isovolumic ferret hearts (n = 9 hypertrophied, n = 9 control) that were loaded with the bioluminescent indicator aequorin to monitor changes in cytoplasmic calcium. In each experiment, left ventricular pressure and intracellular calcium transients were simultaneously recorded. Compared with their age-matched controls, significant hypertrophy of the left ventricle developed 4 weeks after postvalvular aortic banding; at the time the animals were killed, the left ventricular weight/body weight ratio was increased in the banded animals (5.3 x 10(-3) versus 3.6 x 10(-3), p less than 0.001). As indicated by the diastolic pressure-volume relation, left ventricular distensibility was significantly diminished in the hypertrophied hearts. In comparison to the controls, the hypertrophied hearts demonstrated a prolonged duration of isovolumic contraction (time to 90% decline from peak: 278 +/- 5.4 versus 247 +/- 10.2 msec, p less than 0.05), but a marked decrease in peak systolic midwall stress (22.4 +/- 5.0 versus 38.6 +/- 5.7 g/cm2, p less than 0.05). The increased duration of isovolumic contraction correlated with a similar prolongation of the calcium transient (time to 90% decline from peak: 245 +/- 19.5 versus 127 +/- 13.2 msec, p less than 0.05), indicating that the rate of sequestration and perhaps release of calcium by the sarcoplasmic reticulum is decreased in hypertrophy.(ABSTRACT TRUNCATED AT 250 WORDS)

Aequorin↗
PubMed1993

Rat angiotensin II (type 1A) receptor mRNA regulation and subtype expression in myocardial growth and hypertrophy.

Two subtypes of angiotensin II (Ang II) receptors (AT1 and AT2) are distinguished by using the respective specific antagonists. In the present study, we report the regulation of cardiac AT1 type A (AT1A) receptor mRNA levels and the expression pattern of AT1 and AT2 receptors in the growth of the heart and the development and regression of cardiac hypertrophy. The ventricular AT1A mRNA level and the density of Ang II receptors at the neonatal period were significantly increased (3.5-fold and 2.5-fold, respectively) and then downregulated with maturation. The cardiac hypertrophy established in spontaneously hypertensive rats or two-kidney one-clip renovascular hypertensive rats resulted in substantial increases in ventricular AT1A mRNA levels (threefold) and Ang II receptor densities (twofold) as compared with those in respective control rats, whereas the receptor affinity was similar. The proportion of AT1 and AT2 subtypes in the specific Ang II binding in ventricular membranes prepared from normal adult rats was nearly equal. This proportion did not change significantly in the development of myocardial hypertrophy. The regression of cardiac hypertrophy by the normalization of elevated blood pressure completely reversed the increased levels of AT1A mRNA and the receptor density to the control level. Thus, AT1 and AT2 receptors are present in rat ventricular myocardium, and their expression is developmentally regulated and upregulated in response to hypertrophic change. Ang II action exerted through the increased number of Ang II receptors may contribute to the growth of the heart and thus to the maintenance of established hypertrophy as one of the hormones involved in hypertrophy development.

Angiotensin II↗
PubMed1996

Regulation of rDNA transcription during endothelin-1-induced hypertrophy of neonatal cardiomyocytes. Hyperphosphorylation of upstream binding factor, an rDNA transcription factor.

Treatment of cultured neonatal cardiomyocytes with endothelin-1 and phorbol 12-myristate 13-acetate (PMA) results in cardiomyocyte hypertrophy. However, the signal transduction pathways involved in this process are poorly understood. Because increased ribosome biogenesis is a requisite for hypertrophy, we sought to (1) confirm the hypothesis that these two hypertrophic agents did indeed induce rRNA synthesis and (2) examine the mechanism through which this induction was accomplished. In this study, hypertrophy of contraction-arrested neonatal cardiomyocytes induced by treatment with either endothelin-1 or PMA was associated with increased rDNA transcription. Western blots demonstrated that the enhanced rates of rDNA transcription were not mediated by increased amounts of either RNA polymerase I or upstream binding factor (UBF), an rDNA transcription factor. However, immunoprecipitation of [32P] orthophosphate-labeled UBF from hypertrophying neonatal cardiomyocytes suggested that the increased rate of rDNA transcription may be due to the hyperphosphorylation of UBF, which would increase the activity of UBF. The increase in UBF phosphorylation occurred within 3 to 6 hours after exposure to either agent, was maximal at 12 hours, and was sustained for at least the first 24 hours of exposure. Phosphoamino acid analysis of UBF immunoprecipitated from control and treated cardiomyocytes demonstrated that UBF was phosphorylated exclusively on serine residues. Our previous studies have shown that the cellular UBF content increased in adrenergic- and contraction-induced models of cardiac hypertrophy. This study with endothelin-1 and PMA demonstrates that the modulation of UBF phosphorylation is an additional pathway by which ribosome biogenesis may be regulated in neonatal cardiomyocytes. These results support the hypothesis that UBF is an important regulatory factor during the initiation and maintenance of the accelerated rate of rDNA transcription observed during neonatal cardiomyocyte hypertrophy mediated by both phorbol esters and endothelin-1.

Animals↗
PubMed1999

Cellular mechanisms of altered contractility in the hypertrophied heart: big hearts, big sparks.

To investigate the cellular mechanisms for altered Ca2+ homeostasis and contractility in cardiac hypertrophy, we measured whole-cell L-type Ca2+ currents (ICa,L), whole-cell Ca2+ transients ([Ca2+]i), and Ca2+ sparks in ventricular cells from 6-month-old spontaneously hypertensive rats (SHRs) and from age- and sex-matched Wistar-Kyoto and Sprague-Dawley control rats. By echocardiography, SHR hearts had cardiac hypertrophy and enhanced contractility (increased fractional shortening) and no signs of heart failure. SHR cells had a voltage-dependent increase in peak [Ca2+]i amplitude (at 0 mV, 1330+/-62 nmol/L [SHRs] versus 836+/-48 nmol/L [controls], P<0.05) that was not associated with changes in ICa,L density or kinetics, resting [Ca2+]i, or Ca2+ content of the sarcoplasmic reticulum (SR). SHR cells had increased time of relaxation. Ca2+ sparks from SHR cells had larger average amplitudes (173+/-192 nmol/L [SHRs] versus 109+/-64 nmol/L [control]; P<0.05), which was due to redistribution of Ca2+ sparks to a larger amplitude population. This change in Ca2+ spark amplitude distribution was not associated with any change in the density of ryanodine receptors, calsequestrin, junctin, triadin 1, Ca2+-ATPase, or phospholamban. Therefore, SHRs with cardiac hypertrophy have increased contractility, [Ca2+]i amplitude, time to relaxation, and average Ca2+ spark amplitude ("big sparks"). Importantly, big sparks occurred without alteration in the trigger for SR Ca2+ release (ICa,L), SR Ca2+ content, or the expression of several SR Ca2+-cycling proteins. Thus, cardiac hypertrophy in SHRs is linked with an alteration in the coupling of Ca2+ entry through L-type Ca2+ channels and the release of Ca2+ from the SR, leading to big sparks and enhanced contractility. Alterations in the microdomain between L-type Ca2+ channels and SR Ca2+ release channels may underlie the changes in Ca2+ homeostasis observed in cardiac hypertrophy. Modulation of SR Ca2+ release may provide a new therapeutic strategy for cardiac hypertrophy and for its progression to heart failure and sudden death.

Animals↗
PubMed2002

Genetic alterations that inhibit in vivo pressure-overload hypertrophy prevent cardiac dysfunction despite increased wall stress.

BACKGROUND: A long-standing hypothesis has been that hypertrophy is compensatory and by normalizing wall stress acts to maintain normal cardiac function. Epidemiological data, however, have shown that cardiac hypertrophy is associated with increased mortality, thus casting doubt on the validity of this hypothesis. METHODS AND RESULTS: To determine whether cardiac hypertrophy is necessary to preserve cardiac function, we used 2 genetically altered mouse models that have an attenuated hypertrophic response to 8 weeks of pressure overload. End-systolic wall stress (sigma(es)) obtained by sonomicrometry after 1 week of pressure overload showed complete normalization of sigma(es) in pressure-overloaded wild-type mice (287+/-39 versus sham, 254+/-34 g/cm2), whereas the blunted hypertrophic response in the transgenic mice was inadequate to normalize sigma(es) (415+/-81 g/cm2, P<0.05). Remarkably, despite inadequate normalization of sigma(es), cardiac function as measured by serial echocardiography showed little deterioration in either of the pressure-overloaded genetic models with blunted hypertrophy. In contrast, wild-type mice with similar pressure overload showed a significant increase in chamber dimensions and progressive deterioration in cardiac function. Analysis of downstream signaling pathways in the late stages of pressure overload suggests that phosphoinositide 3-kinase may play a pivotal role in the transition from hypertrophy to heart failure. CONCLUSIONS: These data suggest that under conditions of pressure overload, the development of cardiac hypertrophy and normalization of wall stress may not be necessary to preserve cardiac function, as previously hypothesized.

Adenylyl Cyclases↗
PubMed2001

Electrical remodeling in pressure-overload cardiac hypertrophy: role of calcineurin.

BACKGROUND: Myocyte hypertrophy accompanies many forms of heart disease, but its contribution to electrical remodeling is unknown. METHODS AND RESULTS: We studied mouse hearts subjected to pressure overload by surgical thoracic aortic banding. In unbanded control hearts, action potential duration (APD) was significantly longer in subendocardial myocytes compared with subepicardial myocytes. Hypertrophy-associated APD prolongation was significantly greater in subendocardial myocytes compared with subepicardial myocytes, indicating stress-induced amplification of repolarization dispersion. To investigate the underlying basis, we performed voltage-clamp recordings on dissociated myocytes. Under control unoperated conditions, subendocardial myocytes exhibited significantly less transient outward current (I(to)) than did subepicardial cells. Hypertrophy was not associated with significant changes in I(to), sustained current, or inward rectifier current densities, but peak L-type Ca(2+) current density (I(Ca,L)) increased 26% (P<0.05). Recovery from I(Ca,L) inactivation was accelerated in hypertrophied myocytes. Inhibition of calcineurin with cyclosporin A prevented increases in heart mass and myocyte size but was associated with an intermediate APD. The hypertrophy-associated increase in I(Ca,L) and the accelerated recovery from inactivation were blocked by cyclosporin A. CONCLUSIONS: These data reveal regional variation in the electrophysiological response within the left ventricle by way of a mechanism involving upregulated Ca(2+) current and calcineurin. Furthermore, these results reveal partial uncoupling of electrophysiological and structural remodeling in hypertrophy.

Action Potentials↗
PubMed2001

Regulation of thyroid hormone receptor isoforms in physiological and pathological cardiac hypertrophy.

Physiological and pathological cardiac hypertrophy have directionally opposite changes in transcription of thyroid hormone (TH)-responsive genes, including alpha- and beta-myosin heavy chain (MyHC) and sarcoplasmic reticulum Ca(2+)-ATPase (SERCA), and TH treatment can reverse molecular and functional abnormalities in pathological hypertrophy, such as pressure overload. These findings suggest relative hypothyroidism in pathological hypertrophy, but serum levels of TH are usually normal. We studied the regulation of TH receptors (TRs) beta1, alpha1, and alpha2 in pathological and physiological rat cardiac hypertrophy models with hypothyroid- and hyperthyroid-like changes in the TH target genes, alpha- and beta-MyHC and SERCA. All 3 TR subtypes in myocytes were downregulated in 2 hypertrophy models with a hypothyroid-like mRNA phenotype, phenylephrine in culture and pressure overload in vivo. Myocyte TRbeta1 was upregulated in models with a hyperthyroid-like phenotype, TH (triiodothyronine, T3), in culture and exercise in vivo. In myocyte culture, TR overexpression, or excess T3, reversed the effects of phenylephrine on TH-responsive mRNAs and promoters. In addition, TR cotransfection and treatment with the TRbeta1-selective agonist GC-1 suggested different functional coupling of the TR isoforms, TRbeta1 to transcription of beta-MyHC, SERCA, and TRbeta1, and TRalpha1 to alpha-MyHC transcription and increased myocyte size. We conclude that TR isoforms have distinct regulation and function in rat cardiac myocytes. Changes in myocyte TR levels can explain in part the characteristic molecular phenotypes in physiological and pathological cardiac hypertrophy.

Animals↗
PubMed1975

Wall stress and patterns of hypertrophy in the human left ventricle.

It is generally recognized that chronic left ventricular (LV) pressure overload results primarily in wall thickening and concentric hypertrophy, while chronic LV volume overload is characterized by chamber enlargement and an eccentric pattern of hypertrophy. To assess the potential role of the hemodynamic factors which might account for these different patterns of hypertrophy, we measured LV wall stresses throughout the cardiac cycle in 30 patients studied at the time of cardiac catheterization. The study group consisted of 6 subjects with LV pressure overload, 18 with LV volume overload, and 6 with no evidence of heart disease (control). LV pressure, meridional wall stress (sigman), wall thickness (h), and radius (R) were measured in each patient throughout the cardiac cycle. For patients with pressure overload, LV peak systolic and end diastolic pressures were significantly increased (220 plus or minus 6/23 plus or minus 3 mm Hg) compared to control (117 plus or minus 7/10 plus or minus 1 mm Hg, P less than 0.01 for each). However, peak systolic and end diastolic (sigman) were normal (161 plus or minus 24/23 plus or minus 3 times 10-3 dyn/cm-2) compared to control (151 plus or minus 14/17 plus or minus 2 times 10-3 dyn/cm-2, NS), reflecting the fact that the pressure overload was exactly counterbalanced by increased wall thickness (1.5 plus or minus 0.1 cm for pressure overload vs. 0.8 plus or minus 0.1 cm for control, P less than 0.01). For patients with volume overload, peak systolic (sigman) was not significantly different from control, but end diastolic (sigmam) was consistently higher than normal (41 plus or minus 3 times 10-3 dyn/cm-2 for volume overload, 17 plus or minus 2 times 10-3 dyn/cm-2 for control, P less than 0.01). LV pressure overload was associated with concentric hypertrophy, and an increased value for the ratio of wall thickness to radius (h/R ratio). In contrast, LV volume overload was associated with eccentric hypertrophy, and a normal h/R ratio. These data suggest the hypothesis that hypertrophy develops to normalize systolic but not diastolic wall stress. We propose that increased systolic tension development by myocardial fibers results in fiber thickening just sufficient to return the systolic stress (force per unit cross-sectional area) to normal. In contrast, increased resting or diastolic tension appears to result in gradual fiber elongation or lengthening which improves efficiency of the ventricular chamber but cannot normalize the diastolic wall stress.

Adolescent↗
PubMed1991

Decreased Gs alpha mRNA levels accompany the fall in Gs and adenylyl cyclase activities in compensated left ventricular hypertrophy. In heart failure, only the impairment in adenylyl cyclase activation progresses.

We have previously reported that there is a global reduction in adenylyl cyclase associated with a decrement in Gs functional activity in cardiac sarcolemma from animals with pressure overload-induced hypertrophy and heart failure. This study was performed to determine whether hypertrophy alone in the absence of heart failure is sufficient to promote these changes and whether the superimposition of heart failure intensified these changes. Basal and stimulated adenylyl cyclase and Gs activity, as determined in the S49 cyc- reconstitution assay, were measured in sarcolemma from normal (NL), left ventricular hypertrophy (LVH) and heart failure (HF) animals. Simultaneously, we measured the mRNA level encoding for the Gs alpha subunit. These studies indicate that Gs activity and Gs alpha mRNA are decreased by approximately 30% both in the failing heart and even in the heart with compensated hypertrophy before heart failure develops (Gs activity, pmol cyclic AMP/10 min per microgram, NL 4.2 +/- 0.4, LVH 3.0 +/- 0.2, HF 3.2 +/- 0.3; Gs alpha mRNA, pg/10 micrograms RNA, NL 131 +/- 9.0, LVH 104 +/- 7.4, HF 97.4 +/- 9.1; P less than 0.05 as compared with NL for LVH and HF). Accompanying this decrement in Gs activity is a fall in adenylyl cyclase, both basal and stimulated. However, we also identified a further decrease in adenylyl cyclase without any additional change in Gs or in its alpha subunit mRNA level. This is seen only in the sarcolemma from animals with heart failure as compared with those with compensated LV hypertrophy (e.g., NaF-stimulated activity, pmol cyclic AMP/min per mg, NL 420.2 +/- 17.5, LVH 347.1 +/- 29.6, HF 244.2 +/- 27.3; P less than 0.05 compared with NL for LVH and HF, P less than 0.05 compared with LVH for HF). In summary, these studies indicate that both Gs and adenylyl cyclase activities fall in parallel with the development of LV hypertrophy followed by a further decrement in adenylyl cyclase, independent of Gs, in the setting of heart failure.

Adenylyl Cyclases↗