Time-dependent remodeling of transmural architecture underlying abnormal ventricular geometry in chronic volume overload heart failure

To test the hypothesis that the abnormal ventricular geometry in failing hearts may be accounted for by regionally selective remodeling of myocardial laminae or sheets, we investigated remodeling of the transmural architecture in chronic volume overload induced by an aortocaval shunt. We determined three-dimensional finite deformation at apical and basal sites in left ventricular anterior wall of six dogs with the use of biplane cineradiography of implanted markers. Myocardial strains at end diastole were measured at a failing state referred to control to describe remodeling of myofibers and sheet structures over time. After 9 +/- 2 wk (means +/- SE) of volume overload, the myocardial volume within the marker sets increased by >20%. At 2 wk, the basal site had myofiber elongation (0.099 +/- 0.030; P <0.05), whereas the apical site did not [P=not significant (NS)]. Sheet shear at the basal site increased progressively toward the final study (0.040 +/- 0.003 at 2 wk and 0.054 +/- 0.021 at final; both P <0.05), which contributed to a significant increase in wall thickness at the final study (0.181 +/- 0.047; P < 0.05), whereas the apical site did not (P=NS). We conclude that the remodeling of the transmural architecture is regionally heterogeneous in chronic volume overload. The early differences in fiber elongation seem most likely due to a regional gradient in diastolic wall stress, whereas the late differences in wall thickness are most likely related to regional differences in the laminar architecture of the wall. These results suggest that the temporal progression of ventricular remodeling may be anatomically designed at the level of regional laminar architecture.     

The effect of residual strain on the diastolic function of the left ventricle as predicted by a structural model

The unloaded heart is not stress-free. It is subjected to residual stress and strain. Their extent and influence on the global performance of the left ventricle and on local phenomena in the ventricular wall are studied by model simulation. The analysis focuses on the equatorial region of the ventricle, with an approximate thick-walled cylindrical geometry. The in vivo myocardium is considered to be incompressible, consisting of fibers embedded in a fluid matrix, with transmurally varying anisotropic microstructure in accordance with morphological characteristics.

The results show that residual strain is transmurally distributed with a pattern and magnitude which agree well with measurements. The calculated residual strains are within mean ± one standard deviation of the measured ones. Their magnitude was found to increase with increasing opening angle and with increasing wall thickness. The residual strain was found to have several effects on ventricular function: At volumes higher than the reference one it gives rise to more uniform transmural distributions of stress and intramyocardial pressure; it causes about 50% increase in the ventricular compliance at high volumes and doubles the suction of atrial blood at low volumes, thus facilitating the diastolic filling. In addition, residual strains cause bias of in vivo measured strains from their true values. This may significantly affect physiological interpretation of measured ventricular deformations.

In conclusion, the present structural analysis predicts that residual strain has favorable effect on left-ventricular diastolic performance, and gives rise to more uniform ventricular stress distribution.     

Residual strain in ischemic ventricular myocardium.

Structural remodeling during acute myocardial infarction affects ventricular wall stress and strain. To see whether acute myocardial infarction alters residual stress and strain in the left ventricle (LV), we measured opening angles in rat hearts after 30 minutes of left coronary artery occlusion. The mean opening angle in 18 ischemic hearts (51 +/- 20 deg) was significantly greater than in five sham-operated controls (29 +/- 11 deg, P < 0.05). To determine whether these alterations in residual strain may be associated with strain softening caused by systolic overstretch of the noncontracting ischemic tissue, we also measured opening angles in isolated hearts that had been passively inflated to high LV pressures (120 mmHg). The mean opening angle of the strain-softened hearts was not significantly different from the sham-operated hearts (34 +/- 27 deg, P = 0.74). Mean collagen area fractions in the myocardium were not significantly different between ischemic hearts (0.027 +/- 0.014) and the nonischemic group (0.022 +/- 0.011). Although there were significant differences in opening angles measured with ischemia, they do not appear to be a result of altered extracellular collagen content or softening associated with overstretch. Thus, there is a significant change in residual strain associated with acute ischemia that may be related to changes in collagen fiber structure, myocyte structure, or metabolic state.     

Adaptation of passive rat left ventricle in diastolic dysfunction.

This article deals with providing a theoretical explanation for quantitative changes in the geometry, the opening angle and the deformation parameters of the rat ventricular wall during adaptation of the passive left ventricle in diastolic dysfunction. A large deformation theory is applied to analyse transmural stress and strain distribution in the left ventricular wall considering it to be made of homogeneous, incompressible, transversely isotropic, non-linear elastic material. The basic assumptions made for computing stress distributions are that the average circumferential stress and strain for the adaptive ventricle is equal to the average circumferential stress and strain in the normotensive ventricle, respectively.All the relevant parameters, such as opening angle, twist per unit length, axial extension, internal and external radii and others, in the stress-free, unloaded and loaded states of normotensive, hypertensive and adaptive left ventricle are determined. The circumferential stress and strain distribution through the ventricular wall are also computed. Our analysis predicts that during adaptation, wall thickness and wall mass of the ventricle increase. These results are consistent with experimental findings and are the indications of initiation of congestive heart failure.     

Dynamic geometry of the intact left ventricle

Knowledge of left ventricular chamber dynamics is central to our understanding of cardiac physiology. The complicated changes in left ventricular geometry observed in the dog during various phases of the cardiac cycle can be represented as distinct linear relationships between chamber eccentricity and intracavitary volume during diastole and ejection, and probably represent structural properties of the ventricular wall. Chamber geometry of the left ventricle is a major determinant of overall myocardial function. The slope of the radius of curvature (r) to wall thickness (h) relationship is a geometric constant that determines the mural force at any given transmural pressure. Chronic pressure and volume overload produce changes in this geometric relationship as a result of increased mural force resisting ejection. The adaptive mechanism of ventricular hypertrophy in this setting alters the r/h ratio and returns systolic mural force toward normal. Coronary occlusion induces acute changes in regional geometry characterized by holosystolic wall bulging and systolic wall thinning, which shift the r/h relationship upward and to the left. The geometric alteration during ischemia probably increases systolic mural force and could adversely affect myocardial function. Recent studies with patients have shown the r/h ratio to be of value in distinguishing between reversible and irreversible impairment of myocardial performance. Because most myocardial diseases produce major alterations in the structure of the ventricular wall, analysis of dynamic chamber geometry may prove of prognostic value in assessing patients with cardiac disorders.     

Postsurgical changes of the opening angle of canine autogenous vein graft.

The opening angles of 30 canine autogenous vein grafts were measured to determine the postsurgical change of residual strain in the vein graft. Canine femoral veins were grafted to femoral arteries in the end-to-end anastomosis fashion. When harvested, the vein grafts were cut into short segments and the segments were cut open radially. The opened-up configurations were taken as the zero-stress states of the vessels. Opening angle, defined as the angle between the two lines from the middle point to the tips of the inner wall, was used to describe the zero-stress states. Results show that the opening angles (mean +/- SD) are 63.0 +/- 30.6 deg for normal femoral veins, and -0.4 +/- 4.6, 6.1 +/- 19.4, 25.4 +/- 20.1, and 47.8 +/- 11.4 deg for vein grafts at 1 day, 1 week, 4 and 12 weeks postsurgery, respectively. The postsurgical changes in opening angle reveal nonuniform transmural tissue remodeling in the vascular wall. The relations between the changes in opening angle and the changes in the morphology of the vein grafts are discussed. Intimal hyperplasia is correlated to the opening angle and is suggested to be the main factor for the postsurgical increase in opening angle. The longitudinal strain in the vein graft is found to decrease postsurgically.     

An anatomic basis for fetal right ventricular dominance and arterial pressure sensitivity

Fetal right ventricular dominance of flow and arterial pressure sensitivity were recently recognized but controversial findings. We investigated ventricular volumes, weights and dimensions in order to understand if there were anatomic differences between the ventricles which might explain these differential functional findings in the fetal sheep. Forty-four near term lambs and their hearts were weighed. Right and left ventricular free wall weights were not different. Volumes were measured by generating in vitro pressure-volume relations and by casting the two ventricles after fixation at equal, physiologic pressures. Right ventricular volume was greater than left ventricular volume by both techniques. Ventricular interaction and a restraining effect of the pericardium were present. Measurements of the fixed ventricles and their casts revealed the following: left ventricular wall thickness was slightly greater than right ventricular wall thickness; lateral ventricular diameters were not different but anteroposterior ventricular diameters were much greater in the right than left ventricle. Because of these findings, the right ventricular circumferential radii of curvature were greater than for the left ventricle as was the radius to wall thickness ratio. Greater right ventricular volume and radius to wall thickness ratio may be important factors in right ventricular flow dominance and greater sensitivity to arterial pressure.     

Thyroid hormones induce unique and potentially beneficial changes in cardiac myocyte shape in hypertensive rats near heart failure

We examined the effects of thyroid hormones (THs) on left ventricular (LV) function and myocyte remodeling in rats with spontaneously hypertensive heart failure (SHHF). SHHF rats were treated with three different TH doses from 20-21 mo of age. In terminal experiments, LV function (as determined by echocardiography and catheterization) and isolated myocyte shape were examined in SHHF rat groups and age-matched Wistar-Furth control animals. Compared with Wistar-Furth rats, the ratio of alpha- to beta-myosin was reduced in untreated SHHF rats. The alpha-to-beta-myosin ratio increased in all TH groups, which suggests a reversal of the fetal gene program. Low-dose TH produced no changes in LV myocyte size or function, but high-dose TH produced signs of hyperthyroidism (e.g., increased heart weight, tachycardia). The chamber diameter-to-wall thickness ratio declined with increasing dose due to reduced chamber diameter and increased wall thickness. This resulted in a 38% reduction in LV systolic wall stress in the middle- and high-dose groups despite sustained hypertension. Isolated myocyte data indicated that chamber remodeling and reduced wall stress were due to a unique alteration in myocyte transverse shape (e.g., reduced major diameter and increased minor diameter). Based on our present understanding of ventricular remodeling and wall stress, we believe these changes are likely beneficial. Results suggest that TH may be an important regulator of myocyte transverse shape in heart disease.     

Effects of an androgenic steroid on exercise-induced cardiac remodeling in rats.

Habitual exercise results in a rightward shift in left ventricular end diastolic (LVED) pressure-volume or internal dimension (P-D) relationships [left ventricular (LV) remodeling]. However, exercise-mediated LV hypertrophy (LVH) produces an increased LV relative wall thickness [ratio (h/r) of wall thickness (h) to internal radius (r)] and hence a decrement in diastolic wall stress despite LV remodeling. In this study, the effect of chronic administration of an androgenic steroid on exercise-induced LV remodeling and h/r was examined in rats. Habitual exercise on voluntary running wheels resulted in LVH and a rightward shift in the LVED P-D relationships. However, LVH was sufficient to increase LVED h/r. Androgenic steroid administration to exercised rats, without influencing the development of exercise-induced LVH, produced a further rightward shift in the LVED P-D relationship associated with an increased diameter intercept. As a consequence, LVED h/r was reduced to control values. The steroid-mediated effects were not associated with alterations in either the quantity or quality of LV collagen. In conclusion, high-dose androgenic steroid administration alters exercise-induced LV remodeling and subsequently reduces the beneficial effect of physiological LVH on LV h/r.     

Sarcomere length changes in a 3D mathematical model of the pig ventricles

Measurements of the geometry and fibrous-sheet structure of the left and right ventricles of the pig heart are fitted with a finite element model. Mechanical changes during the heart cycle are computed by solving the equations of motion under specified ventricular boundary conditions and using experimentally defined constitutive laws for the active and passive material properties of myocardial tissue. The resulting patterns of deformation, such as axial torsion and changes in wall thickness and base-apex length, are consistent with experimental observations. The model can therefore be used to predict sarcomere length changes and other strain patterns throughout the myocardium and throughout the cardiac cycle. Here we present sarcomere length changes at a limited number of material points within the wall. Sarcomere length typically varies by 10% above and below the unloaded length; although under the boundary conditions imposed in the current model the midwall circumferentially oriented sarcomere lengths increased by up to 20% at end diastole. We provide web-access details for a downloadable software program designed to provide more extensive information on mechanical deformation, such as the principal strains and muscle fibre cross-sectional area changes during the cardiac cycle.     

Border zone geometry increases wall stress after myocardial infarction: contrast echocardiographic assessment

After myocardial infarction (MI), the border zone expands chronically, causing ventricular dilatation and congestive heart failure (CHF). In an ovine model (n = 4) of anteroapical MI that results in CHF, contrast echocardiography was used to image short-axis left ventricular (LV) cross sections and identify border zone myocardium before and after coronary artery ligation. In the border zone at end systole, the LV endocardial curvature (K) decreased from 0.86 +/- 0.33 cm(-1) at baseline to 0.35 +/- 0.19 cm(-1) at 1 h (P < 0.05), corresponding to a mean decrease of 55%. Also in the border zone, the wall thickness (h) decreased from 1.14 +/- 0.26 cm at baseline to 1.01 +/- 0.25 cm at 1 h (P < 0.05), corresponding to a mean decrease of 11%. By Laplace's law, wall stress is inversely proportional to the product K. h. Therefore, a 55% decrease in K results in a 122% increase in circumferential stress; a 11% decrease in h results in a 12% increase in circumferential stress. These findings indicate that after MI, geometric changes cause increased dynamic wall stress, which likely contributes to border zone expansion and remodeling.     

Attenuation of salt-induced cardiac remodeling and diastolic dysfunction by the GPER agonist G-1 in female mRen2.Lewis rats

Introduction

The G protein-coupled estrogen receptor (GPER) is expressed in various tissues including the heart. Since the mRen2.Lewis strain exhibits salt-dependent hypertension and early diastolic dysfunction, we assessed the effects of the GPER agonist (G-1, 40 nmol/kg/hr for 14 days) or vehicle (VEH, DMSO/EtOH) on cardiac function and structure.

Methods

Intact female mRen2.Lewis rats were fed a normal salt (0.5% sodium; NS) diet or a high salt (4% sodium; HS) diet for 10 weeks beginning at 5 weeks of age.

Results

Prolonged intake of HS in mRen2.Lewis females resulted in significantly increased blood pressure, mildly reduced systolic function, and left ventricular (LV) diastolic compliance (as signified by a reduced E deceleration time and E deceleration slope), increased relative wall thickness, myocyte size, and mid-myocardial interstitial and perivascular fibrosis. G-1 administration attenuated wall thickness and myocyte hypertrophy, with nominal effects on blood pressure, LV systolic function, LV compliance and cardiac fibrosis in the HS group. G-1 treatment significantly increased LV lusitropy [early mitral annular descent (e′)] independent of prevailing salt, and improved the e′/a′ ratio in HS versus NS rats (P<0.05) as determined by tissue Doppler.

Conclusion

Activation of GPER improved myocardial relaxation in the hypertensive female mRen2.Lewis rat and reduced cardiac myocyte hypertrophy and wall thickness in those rats fed a high salt diet. Moreover, these advantageous effects of the GPER agonist on ventricular lusitropy and remodeling do not appear to be associated with overt changes in blood pressure.     

DITPA stimulates arteriolar growth and modifies myocardial postinfarction remodeling

Myocardial infarction (MI) is characterized by ventricular remodeling, hypertrophy of the surviving myocardium, and an insufficient angiogenic response. Thyroxine is a powerful stimulus for myocardial angiogenesis. Male rats that underwent coronary artery ligation and subsequent MI were given 3,5-diiodothyropropionic acid (DITPA; MI+DITPA group) during a 3-wk period. We evaluated ventricular remodeling using echocardiography and histology and myocardial vessel growth using image analysis. Protein expression was assessed using Western blotting and immunohistochemistry. This study tested the hypothesis that the thyroxine analog DITPA facilitates angiogenesis and influences postinfarction remodeling in the surviving hypertrophic myocardium. The increase in the region of akinesis (infarct expansion) was blunted in the MI+DITPA rats compared with the MI group (3 vs. 21%); the treated rats had smaller percent increases in the left ventricular (LV) volume (64 +/- 14 vs. 95 +/- 12) and the LV volume-to-mass ratio (47 +/- 13 vs. 84 +/- 10) as well as a blunted decrease in ejection fraction (-9 +/- 8 vs. -30 +/- 7%). Arteriolar length density was higher after treatment in the largest (>50% of the free wall) infarcts (64 +/- 3 vs. 43 +/- 7). Angiogenic growth factors [vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF)] and the angiopoietin receptor tyrosine kinase with immunoglobulin and epidermal growth factor homology domains (Tie-2) values were elevated during the first week after infarction. DITPA did not cause additional increases in VEGF or Tie-2 values but did induce an increase in bFGF value after 3 days of treatment. This study provides the first evidence for an anatomical basis, i.e., attenuated ventricular remodeling and arteriolar growth, for improved function attributed to DITPA therapy of the infarcted heart. The favorable influences of DITPA on LV remodeling after large infarction are principally due to border zone preservation.     

Factors influencing left-ventricular stiffness

The aim of the study was to investigate the relative contributions of geometrical and material factors to overall left-ventricular cavity stiffness. Left-ventricular cavity shapes were reconstructed using a computer and the variation of myocardial elastic modulus was calculated, by the finite element method, through the passive phase of diastole when rising volume coincided with rising pressure. Geometric data were obtained from biplane cineangiography, with micromanometer pressure measurements, for ten patients with left ventricular disease. Dimensional analysis was applied to the initial and derived data from which the influences of myocardial compliance, wall thickness-to-long dimension ratio, and aspect ratio (long-to-short axes) were determined. The ratio between the volume elasticity and the myocardial modulus of elasticity, the normalized stiffness ratio (NSR), is proposed as a useful index of left ventricular mechanical behaviour in diastole. The volume elasticity of the chamber is dependent not only upon the myocardium elastic modulus and the wall thickness ratio, but also on the shape of the chambe. Changes in the thickness/radius ratio of the ventricle have less effect upon its distention than those in the long dimension/radius ratio. The left ventricle becomes more spherical in shpae through diastole and hence becomes stiffer by this geometric mechanism.     

Mutation in collagen gene induces cardiomyopathy in transgenic mice

In many remodeling tissues, such as the heart, collagen degradation to provide new integrin-binding sites is required for survival. However, complete loss of integrin signaling due to disconnection from extracellular matrix (ECM) leads to apoptosis and dilatation. To test the hypothesis that a mutation in type I collagen gene induces cardiomyopathy, we employed a metalloproteinase-resistant collagen mutant homozygous transgenic male (B6,129-Colla-1) and compared with age-sex matched wildtype C57BL/J6 control mice. At the age of 38-42 weeks, aortic and left ventricle (LV) pressure were measured. The LV wall thickness and diameter were measured by a digital micrometer. The levels of matrix metalloproteinase-2 (MMP-2) activity and cardiospecific tissue inhibitor of metalloproteinase-4 (TIMP-4) were measured by zymography and Western blot analyses, respectively. The levels of collagenolysis were measured by Western blot using anti-collagen antibody. In transgenic and wildtype mice, end-diastolic pressure (EDP) was 8.3 +/- 1.7 and 6.5 +/- 1.1 mmHg; LV diameter was 3.43 +/- 0.07 and 2.94 +/- 0.05 mm; wall thickness was 1.18 +/- 0.03 and 1.28 +/- 0.04 mm; end-diastolic wall stress was 600 +/- 158 and 347 +/- 49 dynes/cm(2), respectively. The increase in LV wall stress was associated with increased MMP-2 activity, increased collagenolysis, and decreased levels of TIMP-4. This leads to reduced elastic compliance in collagen mutant transgenic mice. The occurrence of cardiomyopathy in adult Colla-1 mice may be a significant confounding factor as it may be indicative of increased basal levels of ECM disruption. This phenotype is what would be expected if collagen degradation normally supplies integrin ligands during cardiac muscle remodeling.     

Myocardial remodeling after discrete radiofrequency injury: effects of tissue inhibitor of matrix metalloproteinase-1 gene deletion

Discrete myocardial lesions created through the delivery of radiofrequency (RF) energy can expand; however, the mechanisms have not been established. Matrix metalloproteinases (MMPs) play an important role in myocardial remodeling, and MMP activity can be regulated by the tissue inhibitors of the metalloproteinases (TIMPs). This study examined the role of TIMP-1 in postinjury myocardial remodeling. Lesions were created on the left ventricular (LV) epicardium of wild-type (WT, 8-12 wk, 129SVE) and age-matched TIMP-1 gene-deficient (timp-1(-/-)) mice through the delivery of RF current (80 degrees C, 30 s). Heart mass, LV scar volumes, and collagen content were measured at 1 h and 3, 7, and 28 days postinjury (n = 10 each). Age-matched, nonablated mice were used as reference controls (n = 5). Heart mass indexed to tibial length increased in WT and timp-1(-/-) mice but was greater in the timp-1(-/-) mice by 7 days. Scar volumes increased in a time-dependent manner in both groups but were higher in the timp-1(-/-) mice than the WT mice at 7 days (1.48 +/- 0.09 vs. 1.20 +/- 0.11 mm(3).mg(-1).mm, P < 0.05) and remained higher at 28 days. In the remote myocardium, wall thickness was greater and relative collagen content was lower in the timp-1(-/-) mice at 28 days postinjury. Discrete myocardial RF lesions expand in a time-dependent manner associated with myocyte hypertrophy remote to the scar. Moreover, postinjury myocardial remodeling was more extensive with TIMP-1 gene deletion. Thus TIMP-1 either directly or through modulation of MMP activity may regulate myocardial remodeling following infliction of a discrete injury.     

Heart rate reduction by zatebradine reduces infarct size and mortality but promotes remodeling in rats with experimental myocardial infarction

The importance of heart rate for left ventricular remodeling and prognosis after myocardial infarction is not known. We examined the contribution of heart rate reduction by zatebradine, a direct sinus node inhibitor without negative inotropic effects on left ventricular function and dilatation, on mortality, energy metabolism, and neurohormonal changes in rats with experimental myocardial infarction (MI). Thirty minutes after left coronary artery ligation or sham operation, the rats were randomized to receive either placebo or zatebradine (100 mg x kg(-1) x day(-1) per gavage) continued for 8 wk. Mortality during 8 wk was 33.3% in the placebo and 23.0% in the zatebradine group (P < 0.05); MI size was 36 +/- 2% and 30 +/- 1% (means +/- SE, P < 0.05), respectively. Zatebradine improved stroke volume index in all treated rats but increased left ventricular volume in rats with small MI (2.43 +/- 0.10 vs. 1.81 +/- 0.10 ml/kg, P < 0.05) but not in rats with large MI (2.34 +/- 0.09 vs. 2.35 +/- 0.11 ml/kg, not significant). Zatebradine reduced left and right ventricular norepinephrine and increased left and right ventricular 3,4-dihydroxyphenyl ethylene glycol-to-norepinephrine ratio suggesting aggravation of cardiac sympathetic activation by zatebradine after MI. Creatine kinase and lactate dehydrogenase isoenzymes in rats with MI remained unchanged by zatebradine. Lowering heart rate per se reduces mortality and MI size in this model but induces adverse effects on left ventricular remodeling in rats with small MI.     

Dissociation between cardiomyocyte function and remodeling with beta-adrenergic receptor blockade in isolated canine mitral regurgitation

The low-pressure volume overload of isolated mitral regurgitation (MR) is associated with increased adrenergic drive, left ventricular (LV) dilatation, and loss of interstitial collagen. We tested the hypothesis that beta1-adrenergic receptor blockade (beta1-RB) would attenuate LV remodeling after 4 mo of MR in the dog. beta1-RB did not attenuate collagen loss or the increase in LV mass in MR dogs. Using MRI and three-dimensional (3-D) analysis, there was a 70% increase in the LV end-diastolic (LVED) volume-to-LV mass ratio, a 23% decrease in LVED midwall circumferential curvature, and a >50% increase in LVED 3-D radius/wall thickness in MR dogs that was not attenuated by beta1-RB. However, beta1-RB caused a significant increase in LVED length from the base to apex compared with untreated MR dogs. This was associated with an increase in isolated cardiomyocyte length (171+/-5 microm, P<0.05) compared with normal (156+/-3 microm) and MR (165+/-4 microm) dogs. Isolated cardiomyocyte fractional shortening was significantly depressed in MR dogs compared with normal dogs (3.73+/-0.31 vs. 5.02+/-0.26%, P<0.05) and normalized with beta1-RB (4.73+/-0.48%). In addition, stimulation with the beta-adrenergic receptor agonist isoproterenol (25 nM) increased cardiomyocyte fractional shortening by 215% (P<0.05) in beta1-RB dogs compared with normal (56%) and MR (50%) dogs. In summary, beta1-RB improved LV cardiomyocyte function and beta-adrenergic receptor responsiveness despite further cell elongation. The failure to attenuate LV remodeling associated with MR could be due to a failure to improve ultrastructural changes in extracellular matrix organization.     

Thyroid hormone can favorably remodel the diabetic myocardium after acute myocardial infarction

It has been previously shown that regulators of physiological growth such as thyroid hormone (TH) can favorably remodel the post ischaemic myocardium. Here, we further explored whether this effect can be preserved in the presence of co-morbidities such as diabetes which accelerates cardiac remodeling and increases mortality after myocardial infarction. Acute myocardial infarction (AMI) was induced by left coronary ligation in rats with type I diabetes (DM) induced by streptozotocin administration (STZ; 35 mg/kg; i.p.) while sham-operated animals served as controls (SHAM). AMI resulted in distinct changes in cardiac function and geometry; EF% was significantly decreased in DM-AMI [37.9 ± 2.0 vs. 74.5 ± 2.1 in DM-SHAM]. Systolic and diastolic chamber dimensions were increased without concomitant increase in wall thickness and thus, wall tension index [WTI, the ratio of (Left Ventricular Internal Diameter at diastole)/2*(Posterior Wall thickness)], an index of wall stress, was found to be significantly increased in DM-AMI; 2.27 ± 0.08 versus 1.70 ± 0.05. 2D-Strain echocardiographic analysis showed reduced systolic radial strain in all segments, indicating increased loss of cardiac myocytes in the infarct related area and less compensatory hypertrophy in the viable segments. This response was accompanied by a marked decrease in the expression of TRα1 and TRβ1 receptors in the diabetic myocardium without changes in circulating T3 and T4. Accordingly, the expression of TH target genes related to cardiac contractility was altered; β-MHC and PKCα were significantly increased. TH (L-T4 and L-T3) administration prevented these changes and resulted in increased EF%, normal wall stress and increased systolic radial strain in all myocardial segments. Acute myocardial infarction in diabetic rats results in TH receptor down-regulation with important physiological consequences. TH treatment prevents this response and improves cardiac hemodynamics.