Compensatory Left Ventricular Hypertrophy Research Articles

A novel heart failure mice model of hypertensive heart disease by angiotensin II infusion, nephrectomy, and salt loading

Although the mouse heart failure (HF) model of hypertensive heart disease (HHD) is useful to investigate the pathophysiology and new therapeutic targets for HHD, the model using simple experimental procedures and stable phenotypes has not been established. This study aimed to develop a novel mouse HF model of HHD by combining salt loading and uninephrectomy with ANG II infusion. Eight-week-old C57BL/6 male mice were treated with ANG II infusion (AT), ANG II infusion and uninephrectomy (AN), ANG II infusion and salt loading (AS), or ANG II infusion, uninephrectomy, and salt loading (ANS). Systolic blood pressure was significantly elevated and left ventricular (LV) hypertrophy was found in AT, AN, AS, and ANS mice, and there were no significant differences in those parameters between the four groups. At 6 wk after the procedures, only ANS mice showed significant decreases in LV fractional shortening and increases in lung weight with a high incidence. This phenotype was reproducible, and there were few perioperative or early deaths in the experimental procedures. Severe LV fibrosis was found in ANS mice. Oxidative stress was enhanced and small GTPase Rac1 activity was upregulated in the hearts of ANS mice. After the addition of salt loading and uninephrectomy to the ANG II infusion mouse model, cardiac function was significantly impaired, and mice developed HF. This might be a novel and useful mouse HF model to study the transition from compensated LV hypertrophy to HF in HHD.

Abstract 312: STIM1 And The Development Of Pressure-overload Induced Cardiac Hypertrophy In Rodents

STromal Interaction Molecule 1 (STIM1), a membrane protein of the sarcoplasmic reticulum, has recently been proposed as a positive regulator of cardiomyocyte growth by promoting Ca2+ entry through the plasma membrane and the activation of Ca2+-mediated signaling pathways. We studied the role of STIM1 in a pressure-overload induced cardiac hypertrophy model in mice. We observed that STIM1 cardiac expression is increased during left ventricular hypertrophy (LVH) induced by Transverse Aortic Constriction (TAC). We then used recombinant Associated Adenovirus 9 (AAV9) to perform cardiac-targeted gene silencing in vivo. C57Bl/6 mice were injected with saline (noAAV) or with AAV9 expressing shRNA against STIM1 (shSTIM1) at the dose of 1e+11 viral genome which resulted in 70% decrease of STIM1 cardiac expression compared to control mice. Three weeks later, TAC was performed and mice were studied three other weeks later. We found that TAC-shSTIM1 treated mice did not develop LVH compared to noAAV despite the same increase in aortic pressure. Echocardiographic and hemodynamic measurements (see table) showed that TAC-shSTIM1-treated mice had LV dilation and a decreased left ventricular contractile function in line with the absence of compensatory LVH in these mice. Immunohistochemistry demonstrated that LVH prevention was observed at the cellular level with cardiac myocytes cross-section area comparable to sham littermates however with a trend towards more interstitial fibrosis. This study reveals the essential role of STIM1 in the development of compensatory LVH in mice.

Abstract 313: STIM1 Silencing Reverses Pressure-overload Induced Cardiac Hypertrophy In Mice

STromal Interaction Molecule 1 (STIM1), a membrane protein of the sarcoplasmic reticulum, has recently been proposed as a positive regulator of cardiomyocyte growth by promoting Ca2+ entry through the plasma membrane and the activation of Ca2+-mediated signaling pathways. We demonstrated that STIM1 silencing prevented the development of left ventricular hypertrophy (LVH) in rats after abdominal aortic banding. Our aim was to study the role of STIM1 during the transition from LVH to heart failure (HF). For experimental timeline, see figure. Transverse Aortic Constriction (TAC) was performed in C57Bl/6 mice. In vivo gene silencing was performed using recombinant Associated AdenoVirus 9 (AAV9). Mice were injected with saline or with AAV9 expressing shRNA control or against STIM1 (shSTIM1) (dose: 1e+11 viral genome), which decreased STIM1 cardiac expression by 70% compared to control. While cardiac parameters were similar between the TAC groups at weeks 3 and 6, shSTIM1 animals displayed a progressive and total reversion of LVH with LV walls thickness returning to values observed in sham mice at week 8. This reversion was associated with the development of significant LV dilation and severe contractile dysfunction, as assessed by echography. Hemodynamic analysis confirmed the altered contractile function and dilation of shSTIM1 animals. Immunohistochemistry showed a trend to more fibrosis. Despite hypertrophic stimuli, there was a significant reduction in cardiac myocytes cross-section area in shSTIM1-treated animals as compared to other TAC mice. This study showed that STIM1 is essential to maintain compensatory LVH and that its silencing accelerates the transition to HF.

Alteration of Mevalonate Pathway Related Enzyme Expressions in Pressure Overload-Induced Cardiac Hypertrophy and Associated Heart Failure with Preserved Ejection Fraction

Background: Abnormalities of the mevalonate pathway, an important cellular metabolic pathway, are common in many diseases including cardiovascular disease. The mevalonate pathway related enzyme expressions in pressure overload-induced cardiac hypertrophy and associated diastolic dysfunction remains largely unknown. This study aims to investigate whether the expression of mevalonate pathway related enzyme is altered during the progression of cardiac hypertrophy and associated diastolic dysfunction induced by pressure overload. Methods: Male Sprague-Dawley (SD) rats were randomly divided into two groups: the suprarenal abdominal aortic coarctation (AAC) group and the sham group. Results: Histological and echocardiographic assessments showed that there was a significant cardiovascular remodeling in the AAC group compared with the sham group after 3 weeks post-operatively, and the left ventricular (LV) diastolic function was reduced at 8 and 14 weeks post-operatively in the AAC group, without any change in systolic function during the study. The tissue of the heart and the abdominal aorta proximal to the coarctation showed over-expression of several enzymes, including 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR), farnesyl diphosphate synthase (FDPS), farnesyltransferase-α (FNTA), farnesyltransferase-β (FNTB), geranylgeranyltransferase type I (GGTase-I) and the activation of their downstream proteins was enhanced. Conclusions: AAC induced compensatory LV hypertrophy to decompensatory diastolic dysfunction, accompanied by altered expression of several key enzymes in the mevalonate pathway.

AAV9-mediated VEGF-B Gene Transfer Improves Systolic Function in Progressive Left Ventricular Hypertrophy

Mechanisms of the transition from compensatory hypertrophy to heart failure are poorly understood and the roles of vascular endothelial growth factors (VEGFs) in this process have not been fully clarified. We determined the expression profile of VEGFs and relevant receptors during the progression of left ventricular hypertrophy (LVH). C57BL mice were exposed to transversal aortic constriction (TAC) and the outcome was studied at different time points (1 day, 2, 4, and 10 weeks). A clear compensatory phase (2 weeks after TAC) was seen with following heart failure (4 weeks after TAC). Interestingly, VEGF-C and VEGF-D as well as VEGF receptor-3 (VEGFR-3) were upregulated in the compensatory hypertrophy and VEGF-B was downregulated in the heart failure. After treatment with adeno-associated virus serotype 9 (AAV9)-VEGF-B(186) gene therapy in the compensatory phase for 4 weeks the function of the heart was preserved due to angiogenesis, inhibition of apoptosis, and promotion of cardiomyocyte proliferation. Also, the genetic programming towards fetal gene expression, a known phenomenon in heart failure, was partly reversed in AAV9-VEGF-B(186)-treated mice. We conclude that VEGF-C and VEGF-D are associated with the compensatory LVH and that AAV9-VEGF-B(186) gene transfer can rescue the function of the failing heart and postpone the transition towards heart failure.

Aging Aggravates Cardiac Dysfunction in Severe, but not in Mild, Pressure‐Overload

The aging heart undergoes structural and functional alterations, that are reminiscent of changes observed in the failing heart, and which thus may increase the vulnerability of the aging heart to develop heart failure. To investigate the effect of aging on left ventricular (LV) hypertrophy and dysfunction we subjected mice at 3, 12 and 24 mo of age to 8 wk of pressure‐overload produced by transverse aortic constriction (TAC), either mild (mTAC) or severe (sTAC).Aging affected cardiac geometry and function in sham mice, demonstrated by increases in LV weight (~26%) and diameter (~8%) and by decreases in LVdP/dt at 40 mmHg (dP/dtP40) (~13%) and in dP/dtmin (~26%) in 24 mo versus 3 mo old mice (all p<0.05). mTAC produced compensated LV hypertrophy (30–40%) with minimal signs of LV dysfunction, which was similar in all age groups. sTAC resulted in ~75% LV hypertrophy, LV dilation (~20%), global dysfunction and pulmonary congestion in all age groups. However, aging aggravated the responses to sTAC, demonstrated by a further decrease in dP/dtP40 (~30%) and dP/dtmin (~30%) and elevation of lung fluid weight (~27%) and right ventricular weight (~31%) in 24 mo versus 3 mo old mice (all p<0.05). The TAC‐induced increase in expression of atrial natriuretic peptide (ANP) was also most pronounced in the older age groups. In conclusion, the effects of severe pressure‐overload on cardiac hypertrophy and function are aggravated by aging.

Inhibitory kappa-B kinase-β inhibition prevents adaptive left ventricular hypertrophy

BackgroundMost cardiovascular studies have implicated the central transcription factor nuclear factor kappa-B (NF-κB) as contributing to the detrimental effects of cardiac injury. This ostensibly negative view of NF-κB competes with its important role in the normal host inflammatory and immune response. Pressure overload, left ventricular hypertrophy (LVH), and heart failure represent a spectrum of disease that has both adaptive and maladaptive components. In contrast to its known effects related to myocardial ischemia–reperfusion, we hypothesized that NF-κB is necessary for the compensatory phase of cardiac remodeling. MethodsC57BL6 mice underwent minimally invasive transverse aortic constriction with or without inhibition of the proximal NF-κB kinase, inhibitory kappa-B kinase-β. Isolated cardiomyocytes were cultured. Transthoracic echocardiography was performed on all mice. ResultsInhibitory kappa-B kinase-β inhibition successfully decreased cardiomyocyte expression of phosphorylated p65 NF-κB and decreased expression of hypertrophic markers with stimulation in vitro. Three weeks after transverse aortic constriction, the mice treated with inhibitory kappa-B kinase-β inhibition more aggressively developed LVH, as measured by heart weight/body weight ratio, left ventricular mass, and wall thickness. These mice also demonstrated a functional decline, as measured by decreased fractional shortening and ejection fraction. These findings were associated with decreased protein expression of p65 NF-κB. ConclusionsAlthough short-term pressure-overload results in compensatory LVH with normal cardiac function, NF-κB inhibition resulted in increased LVH that was associated with functional deterioration. These observations suggest that NF-κB is an important part of the adaptive phase of LVH, and its inhibition detrimentally affects cardiac remodeling.

Simulation of Exercise-Induced Syncope in a Heart Model with Severe Aortic Valve Stenosis

Severe aortic valve stenosis (AVS) can cause an exercise-induced reflex syncope (RS). The precise mechanism of this syncope is not known. The changes in hemodynamics are variable, including arrhythmias and myocardial ischemia, and one of the few consistent changes is a sudden fall in systemic and pulmonary arterial pressures (suggesting a reduced vascular resistance) followed by a decline in heart rate. The contribution of the cardioinhibitory and vasodepressor components of the RS to hemodynamics was evaluated by a computer model. This lumped-parameter computer simulation was based on equivalent electronic circuits (EECs) that reflect the hemodynamic conditions of a heart with severe AVS and a concomitantly decreased contractility as a long-term detrimental consequence of compensatory left ventricular hypertrophy. In addition, the EECs model simulated the resetting of the sympathetic nervous tone in the heart and systemic circuit during exercise and exercise-induced syncope, the fluctuating intra-thoracic pressure during respiration, and the passive relaxation of ventricle during diastole. The results of this simulation were consistent with the published case reports of exertional syncope in patients with AVS. The value of the EEC model is its ability to quantify the effect of a selective and gradable change in heart rate, ventricular contractility, or systemic vascular resistance on the hemodynamics during an exertional syncope in patients with severe AVS.

Proteome analysis of the left ventricle in the vitamin D3 and nicotine-induced rat vascular calcification model

Vitamin D₃ and nicotine (VDN) serve as an animal model of arterial calcification. The vascular calcification induced by the VDN model is always accompanied by compensatory left ventricular (LV) hypertrophy and impaired cardiac performance. To determine the possible mechanisms that are responsible for the effects of VDN on the LV, a 2-DE based proteomics approach was used to evaluate the changes in protein expression of the left ventricle in VDN rats, to our knowledge, for the first time. We identified sixteen proteins that were markedly altered and involved in mitochondrial function, heat shock protein activity, myocyte cytoskeleton composition and enzyme activity for energy metabolism. We describe, for the first time, a novel pathway (NDPK) that is involved in LV hypertrophy and enzyme activities of three of the sixteen clinical identified proteins: lactate dehydrogenase (LDH), SOD [Mn] and GST.

Loss of myocardial LIF receptor in experimental heart failure reduces cardiotrophin-1 cytoprotection. A role for neurohumoral agonists?

Cardiomyocyte loss is involved in the transition from compensatory left ventricular hypertrophy (LVH) to heart failure (HF). Our aim was to investigate the status of the leukaemia inhibitory factor receptor (LIFR)/gp130 survival pathway and its cytoprotective activity in intact cardiac tissue and in cardiomyocytes obtained from adult spontaneously hypertensive rats (SHR) with LVH (non-failing SHR) and from aged SHR with overt HF (failing SHR). Cardiac morphometry was assayed by planimetry in an image analysis system. mRNA and protein expression were quantified by real time RT-PCR and Western blotting. Receptors were localized by immunocytochemistry. Trypan blue staining, TUNEL, and MTT cell viability assays were employed to study the cytoprotective activity of cardiotrophin-1 (CT-1) in isolated caridomyocytes. Compared to non-failing SHR, failing SHR exhibited enhanced myocardial cell death (p<0.01) demonstrated by the increase in Bax/Bcl-2 ratio, caspase-3 activation and poly (ADP-ribose) polymerase (PARP) fragmentation. Failing SHR had a 7-fold diminished expression (p<0.01) of LIFR, no changes in gp130, and 1.6-fold increased myocardial expression (p<0.01) of CT-1. In cardiomyocytes isolated from non-failing SHR, recombinant CT-1 inhibited apoptotic and non-apoptotic cell death induced by angiotensin II or hydrogen peroxide. LIFR protein was entirely absent in cardiomyocytes isolated from failing SHR, which were resistant to the cytoprotective effects of CT-1. Finally, stimulation of non-failing SHR cardiomyocytes with angiotensin II, aldosterone, norepinephrine or endothelin-1 significantly decreased (p<0.01) LIFR expression. These data suggest that loss of CT-1-dependent survival mechanisms may contribute to the increase of cell death associated with HF in SHR. Neurohumoral activation may contribute to this alteration via suppression of LIFR.

Revisiting Animal Models of Aortic Stenosis in the Early Gestation Fetus

Mechanisms leading to left ventricular hypoplasia and endocardial fibroelastosis in the fetus remain unknown. Prevailing theory is that obstruction to blood flow through the left ventricle leads to elevated end-diastolic pressures, compromised myocardial perfusion, and endocardial ischemia. Fetal interventions are now being performed, based on the presumption that they would prevent such pathogenic mechanisms. Forty first-trimester fetal sheep (mean gestational age, 53 days) were studied. Severe fetal left ventricular outflow obstruction was created by banding the ascending aorta in 25 fetuses; 15 control fetuses underwent "sham" surgery with thoracotomy. Serial fetal echocardiography was used to assess left ventricular growth and fetal hemodynamics. Findings were correlated to morphologic and histopathologic changes, and intracardiac pressure measurements obtained from fetal cardiac catheterization. Surviving banded fetuses (n = 13) had one of two phenotypes: compensatory left ventricular hypertrophy (n = 7) or noncompensatory left ventricular dilatation (n = 6) with hydrops and severe left ventricular dysfunction. All fetuses had elevated left ventricular end-diastolic pressures (mean, 21 mm Hg; range, 14 to 28 mm Hg), which correlated to the gradient across the ascending aorta (mean, 41 mm Hg; range, 28 to 73 mm Hg). In vivo echocardiography findings were incongruous with those at autopsy, and demonstrated preservation of left ventricular growth indices in all fetuses. Endocardial fibroelastosis and myocardial fibrosis were not observed in any banded fetus. While early gestational obstruction to flow can compromise left ventricular function in the fetus, it does not retard normal growth. Similarly, an elevated left ventricular end-diastolic pressure is not sufficient to cause myocardial fibrosis or endocardial fibroelastosis in the fetus.

Cardiac dilatation and pump dysfunction without intrinsic myocardial systolic failure following chronic β-adrenoreceptor activation

There is no direct evidence to indicate that pump dysfunction in a dilated chamber reflects the impact of chamber dilatation rather than the degree of intrinsic systolic failure resulting from myocardial damage. In the present study, we explored the relative roles of intrinsic myocardial systolic dysfunction and chamber dilatation as mediators of left ventricular (LV) pump dysfunction. Administration of isoproterenol, a beta-adrenoreceptor agonist, for 3 mo to rats (0.1 mg.kg(-1).day(-1)) resulted in LV pump dysfunction as evidenced by a reduced LV endocardial fractional shortening (echocardiography) and a decrease in the slope of the LV systolic pressure-volume relation (isolated heart preparations). Although chronic beta-adrenoreceptor activation induced cardiomyocyte damage (deoxynucleotidyl transferase-mediated dUTP nick-end labeling) as well as beta(1)- and beta(2)-adrenoreceptor inotropic downregulation (attenuated contractile responses to dobutamine and salbutamol), these changes failed to translate into alterations in intrinsic myocardial contractility. Indeed, LV midwall fractional shortening (echocardiography) and the slope of the LV systolic stress-strain relation (isolated heart preparations) were unchanged. A normal intrinsic myocardial systolic function, despite the presence of cardiomyocyte damage and beta-adrenoreceptor inotropic downregulation, was ascribed to marked increases in myocardial norepinephrine release, to upregulation of alpha-adrenoreceptor-mediated contractile effects as determined by phenylephrine responsiveness, and to compensatory LV hypertrophy. LV pump failure was attributed to LV dilatation, as evidenced by increased LV internal dimensions (echocardiography), and a right shift and increased volume intercept of the LV diastolic pressure-volume relation. In conclusion, chronic sympathetic stimulation, despite reducing beta-adrenoreceptor-mediated inotropic responses and promoting myocyte apoptosis, may nevertheless induce pump dysfunction primarily through LV dilatation, rather than intrinsic myocardial systolic failure.

Modulation of Contractile Function through Neuropeptide Y Receptors during Development of Cardiomyocyte Hypertrophy

Severity of left ventricular hypertrophy (LVH) correlates with elevated plasma levels of neuropeptide Y (NPY) in hypertension. NPY elicits positive and negative contractile effects in cardiomyocytes through Y(1) and Y(2) receptors, respectively. This study tested the hypothesis that NPY receptor-mediated contraction is altered during progression of LVH. Ventricular cardiomyocytes were isolated from spontaneously hypertensive rats (SHRs) pre-LVH (12 weeks), during development (16 weeks), and at established LVH (20 weeks) and age-matched normotensive Wistar Kyoto (WKY) rats. Electrically stimulated (60 V, 0.5 Hz) cell shortening was measured using edge detection and receptor expression determined at mRNA and protein level. The NPY and Y(1) receptor-selective agonist, Leu(31)Pro(34)NPY, stimulated increases in contractile amplitude, which were abolished by the Y(1) receptor-selective antagonist, BIBP3226 [R-N(2)-(diphenyl-acetyl)-N-(4-hydroxyphenyl)methyl-argininamide)], confirming Y(1) receptor involvement. Potencies of both agonists were enhanced in SHR cardiomyocytes at 20 weeks (2300- and 380-fold versus controls). Maximal responses were not attenuated. BIBP3226 unmasked a negative contraction effect of NPY, elicited over the concentration range (10(-12) to 3 x 10(-9) M) in which NPY and PYY(3-36) attenuated the positive contraction effects of isoproterenol, the potencies of which were increased in cardiomyocytes from SHRs at 20 weeks (175- and 145-fold versus controls); maximal responses were not altered. Expression of NPY-Y(1) and NPY-Y(2) receptor mRNAs was decreased (55 and 69%) in left ventricular cardiomyocytes from 20-week-old SHRs versus age-matched WKY rats; parallel decreases (32 and 80%) were observed at protein level. Enhancement of NPY potency, producing (opposing) contractile effects on cardiomyocytes together with unchanged maximal response despite reduced receptor number, enables NPY to contribute to regulating cardiac performance during compensatory LVH.

Pitavastatin Improves Cardiac Function and Survival in Association With Suppression of the Myocardial Endothelin System in a Rat Model of Hypertensive Heart Failure

Statin therapy may be associated with lower mortality in patients with heart failure, but the underlying mechanism of such an association is unknown. We have evaluated the effects of pitavastatin on cardiac function and survival in a rat model of hypertensive heart failure and investigated the molecular mechanism of the observed effects. Dahl salt-sensitive rats fed with high-salt diet from 7 weeks of age developed compensatory left ventricular hypertrophy at 12 weeks and heart failure at 19 weeks. Dahl salt-sensitive rats were treated with either vehicle or pitavastatin (0.3 mg/kg per day) from 7 or 12 weeks. Both early-onset and late-onset pitavastatin treatment reduced left ventricular fibrosis, improved cardiac function, and increased the survival rate apparent at 19 weeks. The increases in the expression levels of hypertrophic, profibrotic, and metalloproteinase genes as well as in gelatinase activities in the heart induced by the high-salt diet were suppressed by pitavastatin treatment. Furthermore, the level of cardiac endothelin-1 was increased in association with the development of heart failure in a manner sensitive to treatment with pitavastatin. Both early and late pitavastatin treatment thus improved cardiac function and survival, with modulation of extracellular matrix remodeling and endothelin-1 signaling possibly contributing to these beneficial effects.

Impact of T Lymphocytes on Cardiac Remodeling in Hypertension

In their intriguing article appearing in this issue of Hypertension , Yu et al1 provide evidence for a role of T lymphocytes in modulating cardiac matrix remodeling resulting from hypertension. The investigators compared the impact of comparable N G-nitro-l-arginine methyl ester (l-NAME)-induced hypertension on cardiac function and matrix composition among 3 strains of mice with widely different T-lymphocyte profiles. They found increased ventricular stiffness, accompanied by enhanced collagen deposition and cross-linking in the strain of mice that were Th2 dominant (BALB/c). In contrast, in mice that were T- (and B-) lymphocyte deficient (C57BL/6 SCID), hypertension resulted in a diminution of collagen content and cross-linking that was generally associated with heart dilation. No changes in ventricular stiffness or collagen were observed in mice that were Th1 dominant (C57BL/6 WT). Because these different responses of the heart to hypertension were observed under pre-existing dissimilar and extreme immune backgrounds, an obvious question is what impact, if any, T lymphocytes have on hypertension-associated cardiac remodeling in more common scenarios. Will it turn out that the well-established neurohormonal input into cardiac remodeling is actually an immunoneurohormal system or only that the neurohormonal component of remodeling is susceptible to modulation by extreme immune conditions? Other than this broad question, several specific questions come to mind from the work of Yu et al.1 First, how relevant is the use of l-NAME to induce hypertension and cardiac remodeling? Chronic pressure overload of the heart in animal models typically induces changes in the heart that include both increased extracellular matrix deposition and so-called compensatory left ventricular hypertrophy because of enlargement of individual …

Biologie du vieillissement cardiaque et vasculaire

None of the many theories of senescence can account for the aging process in its entirety. These theories include the evolutionary theory of aging and its EvoDevo corollary, the replicative senescence and free radicals theory, theories based on large-scale analyses (proteomics, etc.), and systemic theories. Cardiovascular senescence is first and foremost due to vascular senescence. Aging is associated with enhanced aortic characteristic impedance, which is mainly due to glycation of vessel wall proteins. This increased impedance overloads the left ventricle and causes compensatory left ventricular hypertrophy, usually associated with fibrosis. Extreme aging (> 80 years in humans, > 30 months in rats) is associated with age-related heart failure. Senescence favors heart failure, atrial fibrillation and cardiac hypertrophy. It is also associated with increased systolic pressure and decreased diastolic pressure. The most characteristic features are enhanced pulse pressure and arterial compliance.

Effect of Matrix Metalloproteinase Inhibition by Doxycycline on Myocardial Healing and Remodeling after Myocardial Infarction

The aim of conducting this study was to assess the clinical relevance of matrix metalloproteinase (MMP) inhibition by doxycycline, an effective MMP inhibitor, in a rat model of extensive myocardial infarction (MI) and left ventricular (LV) dysfunction. Rats (n = 22) were subjected to extensive anterior MI. Doxycycline (25 mg SC, daily) or saline (control) injections were started for nine days thereafter. The effect of doxycycline on MMP activity in the infarcted and remote myocardium was measured by zymography, in another subgroup (n = 8), nine days after MI. Echocardiography and magnetic resonance imaging (MRI) studies were performed at one and thirty days after MI to assess LV remodeling and function. After 4 weeks, hearts were fixed, and subjected to morphometric and histological analysis. Compared with control, doxycycline treatment attenuated MMP-9 and -2 activity in both infarcted and remote myocardium. Serial echocardiography studies showed that doxycycline failed to attenuate scar thinning, LV dilatation and dysfunction. MRI study showed that doxycycline impaired LV compensatory hypertrophy. Furthermore, compared with control, doxycycline reduced vessel density (/mm(2) +/- SEM) in the infarcted myocardium (84 +/- 16 vs. 46 +/- 9/mm(2), respectively; p < 0.05). Our work suggest that effective MMPs' inhibition in the infarcted and remote myocardium by doxycycline does not prevent LV remodeling and dysfunction but impairs angiogenesis and compensatory LV hypertrophy. Our findings caution against aggressive, non-selective inhibition of MMPs in the early healing phase after MI.

Positive correlations between serum calcineurin activity and left ventricular hypertrophy

Background Among various intracellular signaling cascades associated with cardiac hypertrophy, the involvement of calcineurin (CaN; Ca 2+-calmodulin dependent protein phosphatase) is gaining credence because of its enhanced activity in ventricular myocardium and the ability of CaN inhibitors to prevent pressure-overload hypertrophy. Since our recent findings attribute clinical significance to serum CaN, the present investigation was conducted to evaluate its significance in cardiac hypertrophy. Methods The study group comprised of patients diagnosed for hypertensive hypertrophy, hypertrophic cardiomyopathy, chronic coronary artery disease with compensatory left ventricular hypertrophy, dilated cardiomyopathy and acute myocardial infarction. Serum contents of CaN and calmodulin were determined and activities of CaN as well as of acid and alkaline phosphatases were assayed and correlated with 2D echocardiography findings. The results were compared with those obtained from age-matched healthy volunteers. Results Serum CaN activity, but not of acid or alkaline phosphatases, was significantly enhanced by 2-fold in hypertensive hypertrophy, 3-fold in hypertrophic cardiomyopathy and 3.75-fold in chronic coronary artery disease associated with left ventricular hypertrophy, unaccompanied by changes in serum contents of calmodulin and CaN. No such increases were observed in acute myocardial infarction and dilated cardiomyopathy. Conclusions Positive correlations observed between serum CaN activity and enhanced left ventricular mass in cardiac hypertrophy suggest that assaying serum CaN activity may be useful in the diagnosis and management of left ventricular hypertrophy.

Bosentan Attenuates Compensatory Left Ventricular Hypertrophy Induced by Aortocaval Fistula in Rats

Background and Objectives:Endothelin-1 (ET-1) is increased in advanced congestive heart failure and pul- monary hypertension associated with increased pulmonary blood flow. The role of ET-1 and the protective effect of the dual endothelin receptor antagonist, Bosentan, were investigated in overcirculation-induced compensatory left ventricular (LV) hypertrophy using aortocaval fistula (AVF) rats. Materials and Methods:Twenty one 8- week-old rats were randomized into sham control, AVF and Bosentan (100 mg/kg/day) treatment groups. Four weeks later, the cardiac hypertrophy, pulmonary artery morphometry, plasma and tissue levels of ET-1 and the immunoreactive signal of ET-1 were evaluated in the heart and lung tissues. Results:Chronic AVF developed LV hypertrophy and markedly increased the plasma and tissue ET-1 levels in the heart and lung compared to those in the controls (p<0.05), and these changes were attenuated by Bosentan treatment (p<0.05). However, the wall thickness of the pulmonary arteriole did not change. In addition, the immunoreactive signal of ET-1 was increased in the heart after AVF compared with the controls, and was also slightly decreased with Bosentan treatment. However, there were no remarkable differences in the lung tissue. Conclusion:ET-1 was up-regulated in compensatory LV hypertrophy induced by AVF. Bosentan attenuates cardiac hypertrophy and decreases the ET-1 levels in the plasma, heart and lung. Therefore, it is speculate that chronic treatment of an ET-1 antagonist may provide an additional strategy for AVF-induced compensatory LV hypertrophy. (Korean Circulation J 2005; 35:665-671)

Biphasic temporal pattern in exercise capacity after myocardial infarction in the rat: relationship to left ventricular remodeling.

After myocardial infarction (MI), there is progressive left ventricular (LV) remodeling and impaired exercise capacity. We tested the hypothesis that LV remodeling results in structural and functional changes that determine exercise impairment post-MI. Rats underwent coronary artery ligation (n = 12) or sham (n = 11) surgery followed by serial exercise tests and echocardiography for 16 wk post-MI. LV pressure-volume relationships were determined using a blood-perfused Langendorff preparation. Exercise capacity was 60% of shams immediately post-MI (P < 0.05) followed by a recovery to near normal during weeks 5-8. Thereafter, there was a progressive decline in exercise capacity to +/-40% of shams (P < 0.01). At both 8 and 16 wk post-MI, fractional shortening (FS) was reduced and end-diastolic diameter (EDD) was increased (P < 0.01). However, neither FS nor EDD correlated with exercise at 8 or 16 wk (r(2) < 0.12, P > 0.30). LV septal wall thickness was increased at both 8 (P = 0.17 vs. shams) and 16 wk (P = 0.035 vs. shams) post-MI and correlated with exercise at both times (r(2) >/= 0.50 and P </= 0.02 at 8 and 16 wk). Neither end-diastolic volume nor maximum LV developed pressure at 16 wk correlated with exercise capacity. Exercise capacity follows a biphasic time course post-MI. An immediate decrease is followed by an early recovery phase that is associated with compensatory LV hypertrophy. Subsequently, there is a progressive decrease in exercise capacity that is independent of further changes in LV volume or contractile function.