Longstanding Hyperthyroidism Is Associated with Normal or Enhanced Intrinsic Cardiomyocyte Function despite Decline in Global Cardiac Function

Thyroid hormones (THs) play a pivotal role in cardiac homeostasis. TH imbalances alter cardiac performance and ultimately cause cardiac dysfunction. Although short-term hyperthyroidism typically leads to heightened left ventricular (LV) contractility and improved hemodynamic parameters, chronic hyperthyroidism is associated with deleterious cardiac consequences including increased risk of arrhythmia, impaired cardiac reserve and exercise capacity, myocardial remodeling, and occasionally heart failure. To evaluate the long-term consequences of chronic hyperthyroidism on LV remodeling and function, we examined LV isolated myocyte function, chamber function, and whole tissue remodeling in a hamster model. Three-month-old F1b hamsters were randomized to control or 10 months TH treatment (0.1% grade I desiccated TH). LV chamber remodeling and function was assessed by echocardiography at 1, 2, 4, 6, 8, and 10 months of treatment. After 10 months, terminal cardiac function was assessed by echocardiography and LV hemodynamics. Hyperthyroid hamsters exhibited significant cardiac hypertrophy and deleterious cardiac remodeling characterized by myocyte lengthening, chamber dilatation, decreased relative wall thickness, increased wall stress, and increased LV interstitial fibrotic deposition. Importantly, hyperthyroid hamsters demonstrated significant LV systolic and diastolic dysfunction. Despite the aforementioned remodeling and global cardiac decline, individual isolated cardiac myocytes from chronically hyperthyroid hamsters had enhanced function when compared with myocytes from untreated age-matched controls. Thus, it appears that long-term hyperthyroidism may impair global LV function, at least in part by increasing interstitial ventricular fibrosis, in spite of normal or enhanced intrinsic cardiomyocyte function.     

Interaction between AT1 and AT2 receptors during postinfarction left ventricular remodeling

The relative contribution of the angiotensin II type 1 and 2 receptors (AT1-R and AT2-R) in postmyocardial infarction (MI) remodeling remains incompletely understood. We studied five groups of C57Bl/6 mice after 1 h of left anterior descending artery occlusion-reperfusion: 1) wild type, untreated (n = 12); 2) wild type, treated with the AT1-R blocker losartan (10-20 mg.kg(-1).day(-1) in drinking water) from day 1 to day 28 post-MI (n = 10); 3) cardiac overexpression of the AT2-R [AT2-transgenic (TG); n = 14]; 4) AT2-TG treated with losartan (n = 13); and 5) AT2-TG and null for the AT1a-R [AT2-TG/AT1 knockout (KO); n = 10]. Cardiac magnetic resonance imaging (CMR) measured ejection fraction and left ventricular end-diastolic and end-systolic volume (EDVI and ESVI) and mass indexed to weight on days 0, 1, 7, and 28 post-MI. Infarct size was measured on day 1 by late gadolinium-enhanced CMR. Regional myocyte hypertrophy and collagen content were measured on day 28 post-MI. Infarct size was similar among groups. Systolic blood pressure was lowest in AT2-TG/AT1KO. By day 28 post-MI, when corrected for baseline differences, EDVI and ESVI were higher and ejection fraction was lower in wild type than other groups. Ejection fraction was highest and EDVI and mass index were lowest in AT2-TG/AT1KO at day 28. The AT2-TG/AT1KO demonstrated less fibrosis in adjacent regions. Regional myocyte hypertrophy was similar in all groups. The AT1-R and AT2-R are intricately intertwined in post-MI remodeling. Pharmacological blockade of AT1-R is equivalent to AT2-R overexpression in attenuating post-MI remodeling. Genetic knockout of the AT1a-R is additive to AT2-R overexpression, due, at least in part, to blood pressure lowering.     

Angiotensin receptor blockade and angiotensin-converting-enzyme inhibition limit adverse remodeling of infarct zone collagens and global diastolic dysfunction during healing after reperfused ST-elevation myocardial infarction

To determine whether therapy with the angiotensin II type 1 receptor blocker (ARB) candesartan and the comparator angiotensin-converting-enzyme inhibitor (ACEI) enalapril during healing after reperfused ST-elevation myocardial infarction (RSTEMI) limit adverse remodeling of infarct zone (IZ) collagens and left ventricular (LV) diastolic dysfunction, we randomized 24 dogs surviving anterior RSTEMI (90-min coronary occlusion) to placebo, candesartan, and enalapril therapy between day 2 and 42. Six other dogs were sham. We measured regional IZ and non-infarct zone (NIZ) collagens (hydroxyproline; types I/III; cross-linking), transforming growth factor-β (TGF-β) and topography at 6 weeks, and hemodynamics, LV diastolic and systolic function, and remodeling over 6 weeks. Compared to sham, placebo-RSTEMI differentially altered regional collagens, with more pronounced increase in TGF-β, hydroxyproline, and type I, insoluble, and cross-linked collagens in the IZ than NIZ, and increased IZ soluble and type III collagens at 6 weeks, and induced persistent LV filling pressure elevation, diastolic and systolic dysfunction, and LV remodeling over 6 weeks. Compared to placebo-RSTEMI, candesartan and enalapril limited adverse regional collagen remodeling, with normalization of type III, soluble and insoluble collagens and decrease in pyridinoline cross-linking in the IZ at 6 weeks, and attenuation of LV filling pressure, diastolic dysfunction, and remodeling over 6 weeks. The results suggest that candesartan and enalapril during healing after RSTEMI prevent rather than worsen adverse remodeling of IZ collagens and LV diastolic dysfunction, supporting the clinical use of ARBs and ACEIs during subacute RSTEMI.     

Selective matrix metalloproteinase inhibition attenuates progression of left ventricular dysfunction and remodeling in dogs with chronic heart failure

Matrix metalloproteinases (MMPs) contribute to the progression of left ventricular (LV) dysfunction and remodeling associated with heart failure (HF). The present study examined the long-term effects of a selective MMP inhibitor PG-530742 (PG) on the progression of LV dysfunction and remodeling in dogs with HF. Chronic HF [LV ejection fraction (LVEF), 相似文献   

Regression of pressure overload-induced left ventricular hypertrophy in mice

As a prelude to investigating the mechanism of regression of pressure overload-induced left ventricular (LV) hypertrophy (LVH), we studied the time course for the development and subsequent regression of LVH as well as accompanying alterations in cardiac function, histology, and gene expression. Mice were subjected to aortic banding for 4 or 8 wk to establish LVH, and regression was initiated by release of aortic banding for 6 wk. Progressive increase in LV mass and gradual chamber dilatation and dysfunction occurred after aortic banding. LVH was also associated with myocyte enlargement, interstitial fibrosis, and enhanced expression of atrial natriuretic peptide, collagen I, collagen III, and matrix metalloproteinase-2 but suppressed expression of alpha-myosin heavy chain and sarcoplasmic reticulum Ca(2+)-ATPase. Aortic debanding completely or partially reversed LVH, chamber dilatation and dysfunction, myocyte size, interstitial fibrosis, and gene expression pattern, each with a distinct time course. The extent of LVH regression was dependent on the duration of pressure overload, evidenced by the fact that restoration of LV structure and function was complete in animals subjected to 4 wk of aortic banding but incomplete in animals subjected to 8 wk of aortic banding. In conclusion, LVH regression comprises a variety of morphological, functional, and genetic components that show distinct time courses. A longer period of pressure overload is associated with a slower rate of LVH regression.     

Therapeutic drugs during healing after myocardial infarction modify infarct collagens and ventricular distensibility at elevated pressures

We investigated whether therapeutic drugs given during healing following acute myocardial infarction (AMI) modify infarct collagens and left ventricular (LV) distensibility. We treated dogs with drugs from major classes (i.e., indomethacin, ibuprofen, captopril, enalapril, verapamil, amlodipine, propranolol, isosorbide dinitrate [ISDN] and digoxin) between day 2 and 6 weeks and measured hemodynamics, LV remodeling and function during healing over 6 weeks after transmural anterior AMI, and regional collagens, LV distensibility under increasing pressure, rupture threshold (RT), and topography at 6 weeks. Relative to sham, AMI controls showed infarct zone (IZ) expansion and thinning, 9.3-fold increase in IZ collagen, LV dilation and dysfunction, and no change in distensibility and RT. Relative to controls, indomethacin as well as enalapril, captopril and amlodipine decreased IZ collagen. Infarct expansion was attenuated by ibuprofen, captopril, amlodipine and ISDN but augmented by indomethacin. Infarct thinning was prevented by captopril, amlodipine and ISDN but enhanced by indomethacin. Importantly, indomethacin and enalapril enhanced LV distensibility and lowered RT. Distensibility correlated positively with IZ type III collagen and negatively with type I/III collagen ratio and pyridinoline cross-links whereas RT correlated positively with IZ type I collagen. Systolic volume and ejection fraction deteriorated with indomethacin but were improved or preserved with other therapies. The results demonstrate that different therapeutic drugs may produce different effects on IZ collagens during healing post-AMI: drugs that attenuate or adversely alter IZ collagens also enhance LV distensibility, augment adverse remodeling and lower RT, suggesting that testing for these effects post-AMI is warranted.     

Beta-1 adrenergic receptor antisense-oligodeoxynucleotides ameliorates left ventricular remodeling in 2-Kidney, 1-Clip rats

Gene therapy has been applied to reduce blood pressure in rats. However, little is known about the effects of gene therapy on both blood pressure and left ventricular (LV) remodeling. This study was designed to compare the antihypertensive effect of ss(1) adrenergic receptor antisense oligodeoxynucleotides (ss(1)- AS-ODN) by delivery with the different charge ratios cationic liposomes DOTAP/DOPE and its impact on the LV remodeling in rats with 2-Kidney, 1-Clip (2K1C) Hypertension. Five charge ratios of liposome/ODN were tested in 2K1C rats. There was hypertension, cardiac dysfunction, LV hypertrophy and LV collagen deposition in 2K1C rats. On the basis of the magnitude and duration of hypotension, 2.0 was determined to be the optimal charge ratio, which decreased blood pressure by up to 39 mm Hg for 27 days. ss(1)-AS-ODN preserved cardiac function and inhibited LV mass and LV interstitial collagen deposition. In conclusion, cationic liposomes DOTAP/DOPE improve the antihypertensive effects of ss(1)-AS-ODN in renovascular hypertension and 2.0 were determined to be the optimal charge ratio. This study demonstrated that cardiac ss(1)-AR played a key role in LV remodeling and ss1-AS-ODN ameliorates cardiac dysfunction and LV remodeling.     

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.     

Prevention of angiotensin II-induced cardiac remodeling by angiotensin-(1-7)

Cardiac remodeling, which typically results from chronic hypertension or following an acute myocardial infarction, is a major risk factor for the development of heart failure and, ultimately, death. The renin-angiotensin system (RAS) has previously been established to play an important role in the progression of cardiac remodeling, and inhibition of a hyperactive RAS provides protection from cardiac remodeling and subsequent heart failure. Our previous studies have demonstrated that overexpression of angiotensin-converting enzyme 2 (ACE2) prevents cardiac remodeling and hypertrophy during chronic infusion of angiotensin II (ANG II). This, coupled with the knowledge that ACE2 is a key enzyme in the formation of ANG-(1-7), led us to hypothesize that chronic infusion of ANG-(1-7) would prevent cardiac remodeling induced by chronic infusion of ANG II. Infusion of ANG II into adult Sprague-Dawley rats resulted in significantly increased blood pressure, myocyte hypertrophy, and midmyocardial interstitial fibrosis. Coinfusion of ANG-(1-7) resulted in significant attenuations of myocyte hypertrophy and interstitial fibrosis, without significant effects on blood pressure. In a subgroup of animals also administered [d-Ala(7)]-ANG-(1-7) (A779), an antagonist to the reported receptor for ANG-(1-7), there was a tendency to attenuate the antiremodeling effects of ANG-(1-7). Chronic infusion of ANG II, with or without coinfusion of ANG-(1-7), had no effect on ANG II type 1 or type 2 receptor binding in cardiac tissue. Together, these findings indicate an antiremodeling role for ANG-(1-7) in cardiac tissue, which is not mediated through modulation of blood pressure or altered cardiac angiotensin receptor populations and may be at least partially mediated through an ANG-(1-7) receptor.     

Combined angiotensin receptor blocker and ACE inhibitor on myocardial fibrosis and left ventricular stiffness in dogs with heart failure

Angiotensin receptor blocker (ARB) and angiotensin-converting enzyme (ACE) inhibitor (ACEI) each act in a different manner to prevent myocardial fibrosis and left ventricular (LV) stiffness in animals with pathways in the heart for generating ANG II as well as ACE. A model of pacing-induced congestive heart failure (CHF) was used to test the central hypothesis that ARB + ACEI prevents myocardial fibrosis and decreases LV stiffness to a greater extent than ARB or ACEI alone. Thirty-five dogs were assigned to the following treatment protocols on the 8th day of a 4-wk pacing schedule: 1) rapid ventricular pacing, 2) ARB (candesartan cilexetil, 1.5 mg.kg(-1).day(-1)) with pacing, 3) ACEI (enalapril, 1.9 mg.kg(-1).day(-1)) with pacing, 4) ARB (candesartan cilexetil, 0.75 mg.kg(-1).day(-1)) + ACEI (enalapril, 0.95 mg.kg(-1).day(-1)) with pacing, and 5) sham operation. The LV stiffness coefficient was significantly increased after rapid pacing but was significantly lower with ARB + ACEI than with ARB or ACEI alone. The collagen volume fraction and mRNA levels of collagen I and III, which were increased by rapid pacing, were significantly lower with ARB + ACEI than with ARB or ACEI alone. Thus ARB + ACEI prevents myocardial fibrosis and decreases LV stiffness during the progression of CHF compared with ARB or ACEI alone.     

Gender-specific patterns of left ventricular and myocyte remodeling following myocardial infarction in mice deficient in the angiotensin II type 1a receptor

Left ventricular (LV) remodeling after myocardial infarction (MI) results from hypertrophy of myocytes and activation of fibroblasts induced, in part, by ligand stimulation of the ANG II type 1 receptor (AT1R). The purpose of the present study was to explore the specific role for activation of the AT 1a R subtype in post-MI remodeling and whether gender differences exist in the patterns of remodeling in wild-type and AT 1a R knockout (KO) mice. AT 1a R-KO mice and wild-type littermates underwent coronary ligation to induce MI or sham procedures; echocardiography and hemodynamic evaluation were performed 6 wk later, and LV tissue was harvested for infarct size determination, morphometric measurements, and gene expression analysis. Survival and infarct size were similar among all male and female wild-type and AT 1a R-KO mice. Hemodynamic indexes were also similar except for lower systolic blood pressure in the AT 1a R-KO mice compared with wild-type mice. Male and female wild-type and male AT 1a R-KO mice developed similar increases in LV chamber size, LV mass corrected for body weight (LV/BW), and myocyte cross-sectional area (CSA). However, female AT 1a R-KO mice demonstrated no increase in LV/BW and myocyte CSA post-MI compared with shams. Both male and female wild-type mice demonstrated higher atrial natriuretic peptide (ANP) levels after MI, with female wild types being significantly greater than males. However, male and female AT 1a R-KO mice developed no increase in ANP gene expression with MI despite an increase in LV mass and myocyte size in males. These data support that gender-specific patterns of LV and myocyte hypertrophy exist after MI in mice with a disrupted AT 1a R gene, and suggest that myocyte hypertrophy post-MI in females relies, in part, on activation of the AT 1a R. Further work is necessary to explore the potential mechanisms underlying these gender-based differences.     

Preventive Effect of Yuzu and Hesperidin on Left Ventricular Remodeling and Dysfunction in Rat Permanent Left Anterior Descending Coronary Artery Occlusion Model

Left ventricular (LV) remodeling, which includes ventricular dilatation and increased interstitial fibrosis after myocardial infarction (MI), is the critical process underlying the progression to heart failure. Therefore, a novel approach for preventing LV remodeling after MI is highly desirable. Yuzu is a citrus plant originating in East Asia, and has a number of cardioprotective properties such as hesperidin. However, no study has proved whether yuzu can prevent LV remodeling. The aim of this study was to determine the effects of yuzu on heart failure (HF) and its potential impact on the LV remodeling process after MI. Our in vivo study using the permanent left anterior descending coronary artery (LAD) occlusion model demonstrate that one week pre-treatment with yuzu or its major metabolite hesperidin before LAD occlusion significantly attenuated cardiac dysfunction, myocyte apoptosis and inflammation. Not only yuzu but also hesperidin inhibited caspase-3 activity, myeloperoxidase expression, α-smooth muscle actin expression, and matrix metalloproteinase-2 activity in a permanent LAD occlusion rat model. To our knowledge, our findings provide the first evidence that yuzu and hesperidin prevent MI-induced ventricular dysfunction and structural remodeling of myocardium.     

Expression of matrix metalloproteinase activity in idiopathic dilated cardiomyopathy: A marker of cardiac dilatation

BACKGROUND: Idiopathic dilated cardiomyopathy (DCM), ventricular systolic dysfunction and chamber dilatation are accompanied by architectural remodeling, wall thinning and cardiac myocyte slippage. Recent work has demonstrated an association between collagen degradation and an increased expression of matrix metalloproteinases (MMPs). Accordingly, we have sought to correlate (a) collagen degradation with MMP elevations and, (b) assay the neutralizing potential of a known inhibitor of MMP, tetracycline on MMPs in DCM. METHODS: Assessment of LV volume and shape by 2-D echocardiography was performed. Light microscopic assessment of histopathology in picrosirius red stained biopsy samples of 11 DCM patients and six post-transplant patients was performed. Zymographic estimation of MMP activity and influence of tetracycline on MMP activity was assessed. RESULTS: Small amount of interstitial collagen was noted in the control group, whereas in the DCM hearts, chamber dilatation was associated with areas of scanty myocyte necrosis, islands of excess collagen, and focal areas of absent or scanty collagen with intact myocytes. In cardiomyopathic tissue, collagenase activity was markedly elevated at 63% compared with 8% in post-transplant tissue. Tetracycline at a concentration of 285+/-10 microM (IC50) inhibited collagenase activity by 50% in cardiomyopathic tissue. CONCLUSIONS: Areas of focal interstitial collagen accumulation were accompanied by collagen fiber lysis and increased collagenase activity in dilated cardiomyopathy. This enhanced collagenolytic activity found in endomyocardial biopsy tissue was inhibited by tetracycline. The non-antibiotic property of tetracycline may be of potential value in the prevention of ventricular dilatation in idiopathic dilated cardiomyopathy.     

Expression of matrix metalloproteinase activity in idiopathic dilated cardiomyopathy: A marker of cardiac dilatation

Background: Idiopathic dilated cardiomyopathy (DCM), ventricular systolic dysfunction and chamber dilatation are accompanied by architectural remodeling, wall thinning and cardiac myocyte slippage. Recent work has demonstrated an association between collagen degradation and an increased expression of matrix metalloproteinases (MMPs). Accordingly, we have sought to correlate (a) collagen degradation with MMP elevations and, (b) assay the neutralizing potential of a known inhibitor of MMP, tetracycline on MMPs in DCM. Methods: Assessment of LV volume and shape by 2-D echocardiography was performed. Light microscopic assessment of histopathology in picrosirius red stained biopsy samples of 11 DCM patients and six post-transplant patients was performed. Zymographic estimation of MMP activity and influence of tetracycline on MMP activity was assessed. Results: Small amount of interstitial collagen was noted in the control group, whereas in the DCM hearts, chamber dilatation was associated with areas of scanty myocyte necrosis, islands of excess collagen, and focal areas of absent or scanty collagen with intact myocytes. In cardiomyopathic tissue, collagenase activity was markedly elevated at 63% compared with 8% in post-transplant tissue. Tetracycline at a concentration of 285 ± 10 μM (IC50) inhibited collagenase activity by 50% in cardiomyopathic tissue. Conclusions: Areas of focal interstitial collagen accumulation were accompanied by collagen fiber lysis and increased collagenase activity in dilated cardiomyopathy. This enhanced collagenolytic activity found in endomyocardial biopsy tissue was inhibited by tetracycline. The non-antibiotic property of tetracycline may be of potential value in the prevention of ventricular dilatation in idiopathic dilated cardiomyopathy. (Mol Cell Biochem 264: 183–191, 2004)     

Interaction between bradykinin subtype 2 and angiotensin II type 2 receptors during post-MI left ventricular remodeling

Angiotensin II type 2 receptor (AT(2)R) overexpression (AT(2)TG) attenuates left ventricular remodeling in a mouse model of anterior myocardial infarction (MI). We hypothesized that the beneficial effects of cardiac AT(2)TG are mediated via the bradykinin subtype 2 receptor (B(2)R). Fourteen transgenic mice overexpressing the AT(2)R (AT(2)TG mice), 10 mice with a B(2)R deletion (B(2)KO mice), 13 AT(2)TG mice with B(2)R deletion (AT(2)TG/B(2)KO mice), and 11 wild-type (WT) mice were studied. All mice were on a C57BL/6 background. Mice were studied by cardiac magnetic resonance imaging at baseline and days 1, 7, and 28 after MI induced by 1 h of occlusion of the left anterior descending artery followed by reperfusion. Short-axis images from apex to base were used to compare ventricular volumes and ejection fraction (EF). At baseline, end-diastolic volume index (EDVI) and end-systolic volume index (ESVI) were lower and EF higher in AT(2)TG mice compared with the other three strains. Infarct size was similar between groups. No differences were observed in global remodeling parameters at day 28 between AT(2)TG and AT(2)TG/B(2)KO mice; however, EDVI and ESVI were lower and EF higher in both transgenic groups than in WT or B(2)KO mice. Both strains lacking B(2)R demonstrated increased collagen content and less hypertrophy in adjacent noninfarcted regions at day 28. Attenuation of postinfarct remodeling by overexpression of AT(2)R is not directly mediated via a B(2)R pathway. However, B(2)R does appear to have a role in the smaller cavity size and hyperdynamic function observed at baseline in AT(2)TG mice and in limiting collagen deposition during postinfarct remodeling.     

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.     

Hyperhomocysteinemia leads to pathological ventricular hypertrophy in normotensive rats

A recent report indicated that hyperhomocysteinemia (Hhe), in addition to its atherothrombotic effects, exacerbates the adverse cardiac remodeling seen in response to hypertension, a powerful stimulus for pathological ventricular hypertrophy. The present study was undertaken to determine whether Hhe has a direct effect on ventricular remodeling and function in the absence of other hypertrophic stimuli. Male Wistar-Kyoto rats were fed either an amino acid-defined control diet or an intermediate Hhe-inducing diet. After 10 wk of dietary treatment, rats were subjected to echocardiographic assessment of left ventricular (LV) dimensions and systolic function. Subsequently, blood was collected for plasma homocysteine measurements, and the rats were killed for histomorphometric and biochemical assessment of cardiac remodeling and for in vitro cardiac function studies. Significant LV hypertrophy was detected by echocardiographic measurements, and in vitro results showed hypertrophy with significantly increased myocyte size in the LV and right ventricle (RV). LV and RV remodeling was characterized by a disproportionate increase in perivascular and interstitial collagen, coronary arteriolar wall thickening, and myocardial mast cell infiltration. In vitro study of LV function demonstrated abnormal diastolic function secondary to decreased compliance because the rate of relaxation did not differ between groups. LV systolic function did not vary between groups in vitro. In summary, in the absence of other hypertrophic stimuli short-term intermediate Hhe caused pathological hypertrophy and remodeling of both ventricles with diastolic dysfunction of the LV. These results demonstrate that Hhe has direct adverse effects on cardiac structure and function, which may represent a novel direct link between Hhe and cardiovascular morbidity and mortality, independent of other risk factors.     

Analysis of postextrasystolic relaxation response in the human heart

Postextrasystolic potentiation is the phenomenon in which ventricular contractile force is strengthened by a preceding premature beat. However, the response of diastolic function after an extrasystole is unknown. We studied 58 patients with chronic heart failure (CHF) and two control subjects to evaluate the response of relaxation following extrasystole. At cardiac catheterization, from the derivative of the left ventricular (LV) pressure, the ratio of LV peak negative dP/dt (–dP/dt) of a postextrasystole to a basal beat was calculated and defined as the postextrasystolic relaxation response (PRR). PRR was compared with parameters of left ventriculography: LV end-diastolic volume index (EDVI), LV end-systolic volume index (ESVI), and LV ejection fraction (EF). The PRRs of the two control subjects were 0.80 and 0.84. The mean PRR of the CHF patients was 0.99 ± 0.15. In all subjects, including patients and controls, correlation analysis between (EDVI, ESVI, and EF) and PRR yielded the following: (a) EDVI vs. PRR: R = 0.273, p = 0.036; (b) ESVI vs. PRR: R = 0.446, p < 0.001; and (c) EF vs. PRR: R = –0.520, p < 0.001. Thus, normal or non-failing human hearts showed a decline of –dP/dt in postextrasystole compared with the basal beats, but failing hearts had potentiated relaxation following an extrasystole.     

Temporal pattern of left ventricular structural and functional remodeling following reversal of volume overload heart failure

Current surgical management of volume overload-induced heart failure (HF) leads to variable recovery of left ventricular (LV) function despite a return of LV geometry. The mechanisms that prevent restoration of function are unknown but may be related to the timing of intervention and the degree of LV contractile impairment. This study determined whether reduction of aortocaval fistula (ACF)-induced LV volume overload during the compensatory stage of HF results in beneficial LV structural remodeling and restoration of pump function. Rats were subjected to ACF for 4 wk; a subset then received a load-reversal procedure by closing the shunt using a custom-made stent graft approach. Echocardiography or in vivo pressure-volume analysis was used to assess LV morphology and function in sham rats; rats subjected to 4-, 8-, or 15-wk ACF; and rats subjected to 4-wk ACF followed by 4- or 11-wk reversal. Structural and functional changes were correlated to LV collagen content, extracellular matrix (ECM) proteins, and hypertrophic markers. ACF-induced volume overload led to progressive LV chamber dilation and contractile dysfunction. Rats subjected to short-term reversal (4-wk ACF + 4-wk reversal) exhibited improved chamber dimensions (LV diastolic dimension) and LV compliance that were associated with ECM remodeling and normalization of atrial and brain natriuretic peptides. Load-independent parameters indicated LV systolic (preload recruitable stroke work, Ees) and diastolic dysfunction (tau, arterial elastance). These changes were associated with an altered α/β-myosin heavy chain ratio. However, these changes were normalized to sham levels in long-term reversal rats (4-wk ACF + 11-wk reversal). Acute hemodynamic changes following ACF reversal improve LV geometry, but LV dysfunction persists. Gradual restoration of function was related to normalization of eccentric hypertrophy, LV wall stress, and ECM remodeling. These results suggest that mild to moderate LV systolic dysfunction may be an important indicator of the ability of the myocardium to remodel following the reversal of hemodynamic overload.