Left ventricular cellular hypertrophy in pressure- and volume-overload valvular heart disease

To determine the dependence of myocyte hypertrophy in chronic valvular heart disease on the site and type of lesion, the myocardium was studied from 11 patients with either pressure-overload hypertrophy (PO; four patients with aortic stenosis and two with mixed aortic stenosis/insufficiency) or pure volume-overload hypertrophy (VO; two patients with mitral regurgitation and three with aortic insufficiency). These patients, all without coronary artery disease, died zero to 34 days after valve replacement surgery. Diameters of 25 longitudinally oriented myocytes in the circular midwall myocardium were measured with a calibrated light microscope eyepiece reticle on each of five transmural, transverse, histologic sections from the apical, anterolateral, posterolateral, anteroseptal, and posteroseptal left ventricle. Statistical analysis by modified two-way analysis of variance (ANOVA) demonstrated that mean myocyte size (based on 125 measurements) varied widely among cases but was not statistically different among sites. The myocyte diameter for PO lesions (25.9 +/- 1.1 micron, mean +/- SEM) was significantly greater (P less than 0.05) than that for pure VO lesions (20.4 +/- 0.7 micron), despite equal relative heart weights (measured/predicted from body weight: 2.5 +/- 0.2 [mean +/- SD] versus 2.5 +/- 0.5). This study suggests that 1) cellular hypertrophy in valvular heart disease occurs uniformly throughout the left ventricular myocardium; and 2) mean myocyte diameters are greater in PO than in VO hypertrophy for equivalent cardiac enlargement.     

Pathologic changes in the long-term transplanted heart: a morphometric study of myocardial hypertrophy, vascularity, and fibrosis

Myocyte hypertrophy and myocardial fibrosis have been observed in transplanted human hearts, and both could potentially have an adverse effect on long-term cardiac function. There has been some concern that distant donor heart procurement and cyclosporine treatment increase the risk of these changes, but their incidence and severity have not been documented quantitatively in large numbers of cardiac transplant recipients. We used light microscopic morphometric methods to estimate myocardial collagen volume fraction and myocyte width in right ventricular endomyocardial biopsies from 95 recipients at 3 years posttransplantation, and electron microscopic stereology to estimate myocardial vascularity and myocyte myofibril content in 40 recipients, also at 3 years posttransplantation. We compared those with locally and distantly procured donor hearts (mean ischemic time 160 minutes) and cyclosporine versus noncyclosporine immunosuppression. Controls were pretransplant right ventricular biopsies from 20 donor hearts which were free of heart disease. We found no significant differences in myocardial collagen volume fractions. Myocyte hypertrophy was typical of all the transplant biopsies (mean myocyte width 20.2 microns, SD 3.0 in all transplants versus 11.8 microns, SD 2.2 in controls, P less than 0.001), but distant donor procurement and cyclosporine had no significant effect. There were significant reductions of myofibril volume fraction in the transplants, which raises the possibility of gradual decompensation in some patients. There were no significant differences in myocardial vascularity, although a few patients were well below the control range. We conclude that distant donor heart procurement, with ischemic times averaging less than 3 hours, and cyclosporine treatment are not responsible for significant hypertrophy or fibrosis in most transplants. Hypertrophy is typical of the transplanted heart, and it is possible that associated abnormalities might have an effect on cardiac function in some long-term survivors.     

Alcohol-induced myocardial fibrosis in metallothionein-null mice: prevention by zinc supplementation

Alcohol-induced cardiomyopathy including fibrosis has been recognized clinically for a long time, but its pathogenesis is incompletely understood. Studies using experimental animals have not fully duplicated the pathological changes in humans, and animal models of alcoholic cardiac fibrosis are not available. In the present study, we have developed a mouse model in which cardiac hypertrophy and fibrosis were produced in metallothionein-knockout (MT-KO) mice fed an alcohol-containing liquid diet for 2 months. The same alcohol feeding did not produce cardiac fibrosis in the wild-type (WT) control mice, although there was no difference in the alcohol-induced heart hypertrophy between the WT controls and the MT-KO mice. Zinc supplementation prevented cardiac fibrosis but did not affect heart hypertrophy in the alcohol-fed MT-KO mice, suggesting a specific link between zinc homeostasis and cardiac fibrosis. Serum creatine phosphokinase activity was significantly higher in the alcohol-administered MT-KO mice than in the WT mice, and zinc supplementation decreased serum creatine phosphokinase activities and eliminated the difference between the groups. Thus, disturbance in zinc homeostasis due to the lack of MT associates with alcohol-induced cardiac fibrosis and more severe cardiac injury, making the MT-KO mouse model of alcohol-induced cardiac fibrosis a useful tool to investigate specific factors involved in the alcoholic cardiomyopathy.     

Hypertensive Pulmonalarterienveränderungen bei chronisch-entzündlichen Lungenerkrankungen

Summary 150 cases of chronic inflammatory lung diseases of unknown aetiology and assumed hyperergic (immuno-reactive) pathogenesis were examined for hypertensive pulmonary arterial lesions and for chronic cor pulmonale. Hypertensive lesions of the small pulmonary arteries were found in more than half of the cases with chronic disorders of long duration, but were inconspicuous in diseases of acute progressive character. Hypertensive lesions were found regularly in chronic interstitial pneumonia, frequently in scleroderma and rheumatoid arthritis and occasionally in dermatomyositis and disseminated lupus erythematosus. Chronic Cor pulmonale occurred in 16% of the cases with hypertensive arterial lesions of grade I (hypertrophy of media) and in 50% of grade II/III (hypertrophy of media and intimai fibrosis). Interstitial lung fibrosis plays an important role in the pathogenesis of cor pulmonale: two thirds of the cases with interstitial lung fibrosis had developed cor pulmonale and all the cases with cor pulmonale also had interstitial lung fibrosis.Hypertensive arterial lesions of grade IV–VI according to Heath and Edwards (angiitis, plexogenic and angiomatoid lesions) have been described in severe cases of pulmonary hypertension (congenital cardiac shunts, primary pulmonary hypertension). In secondary forms of pulmonary hypertension, as represented by our material, these changes are of little importance.

     

心肌L型钙通道/电流及其在心肌肥大和心力衰竭时的变化

心肌细胞电活动的基础就是各种通道的离子流。有两类离子流左右心肌细胞的电活动 :一类是内向离子流 ,包括Ｉｎａ、Ｉｎａ-ｂ、Ｉｆ、Ｉｃａ-Ｌ、Ｉｃａ-Ｔ;另一类是外向离子流 ,包括Ｉｔｏ(Ｉｔｏ1 、Ｉｔｏ2 )、ＩＫ(ＩＫｒ、ＩＫｓ、Ｉｋｐ)、ＩＫ1 、ＩＫ -ＡＴＰ、ＩＫ -Ａｃｈ等。心肌细胞的钙通道 /电流属内向电流 ,可分为两大类 :(1 )Ｌ型Ｃａ2 通道 /电流(ＩＣａ-Ｌ) ,它在决定心肌细胞动作电位平台期的内向电流和启动心肌细胞兴奋 -收缩耦联都发挥极其重要的作用。 (2 )Ｔ型Ｃａ2 通道 /电流 (Ｉｃａ-Ｔ) ,它可能在心脏起搏细胞…     

Adult cardiac fibroblast proliferation is modulated by calcium/calmodulin-dependent protein kinase II in normal and hypertrophied hearts

Increased adult cardiac fibroblast proliferation results in an increased collagen deposition responsible for the fibrosis accompanying pathological remodelling of the heart. The mechanisms regulating cardiac fibroblast proliferation remain poorly understood. Using a minimally invasive transverse aortic banding (MTAB) mouse model of cardiac hypertrophy, we have assessed fibrosis and cardiac fibroblast proliferation. We have investigated whether calcium/calmodulin-dependent protein kinase IIδ (CaMKIIδ) regulates proliferation in fibroblasts isolated from normal and hypertrophied hearts. It is known that CaMKIIδ plays a central role in cardiac myocyte contractility, but nothing is known of its role in adult cardiac fibroblast function. The MTAB model used here produces extensive hypertrophy and fibrosis. CaMKIIδ protein expression and activity is upregulated in MTAB hearts and, specifically, in cardiac fibroblasts isolated from hypertrophied hearts. In response to angiotensin II, cardiac fibroblasts isolated from MTAB hearts show increased proliferation rates. Inhibition of CaMKII with autocamtide inhibitory peptide inhibits proliferation in cells isolated from both sham and MTAB hearts, with a significantly greater effect evident in MTAB cells. These results are the first to show selective upregulation of CaMKIIδ in adult cardiac fibroblasts following cardiac hypertrophy and to assign a previously unrecognised role to CaMKII in regulating adult cardiac fibroblast function in normal and diseased hearts.     

Deferasirox and deferiprone remove cardiac iron in the iron-overloaded gerbil

Introduction: Deferasirox effectively controls liver iron concentration; however, little is known regarding its ability to remove stored cardiac iron. Deferiprone seems to have increased cardiac efficacy compared with traditional deferoxamine therapy. Therefore, the relative efficacy of deferasirox and deferiprone were compared in removing cardiac iron from iron-loaded gerbils. METHODS: Twenty-nine 8- to 10-week-old female gerbils underwent 10 weekly iron dextran injections of 200 mg/kg/week. Prechelation iron levels were assessed in 5 animals, and the remainder received deferasirox 100 mg/kg/D po QD (n = 8), deferiprone 375 mg/kg/D po divided TID (n = 8), or sham chelation (n = 8), 5 days/week for 12 weeks. RESULTS: Deferasirox reduced cardiac iron content 20.5%. No changes occurred in cardiac weight, myocyte hypertrophy, fibrosis, or weight-to-dry weight ratio. Deferasirox treatment reduced liver iron content 51%. Deferiprone produced comparable reductions in cardiac iron content (18.6% reduction). Deferiprone-treated hearts had greater mass (16.5% increase) and increased myocyte hypertrophy. Deferiprone decreased liver iron content 24.9% but was associated with an increase in liver weight and water content. CONCLUSION: Deferasirox and deferiprone were equally effective in removing stored cardiac iron in a gerbil animal model, but deferasirox removed more hepatic iron for a given cardiac iron burden.     

Sarcoidosis and immunoglobulin lambda II light-chain amyloidosis diagnosed after orthotopic heart transplantation: a case report and review of the literature.

Cardiac involvement by sarcoidosis and concomitant deposition of AL amyloid is an uncommon association. We describe the case of a 53-year-old African-American man with a 7-year history of dilated nonischemic cardiomyopathy and severe cardiac failure who underwent orthotopic heart transplantation. His prior cardiac biopsies had only mild myocyte hypertrophy and minimal interstitial fibrosis. After surgery, numerous sarcoid granulomas and amyloid deposition were identified in the native heart. Six days after the transplant the patient died due to aspiration bronchopneumonia and acute renal failure. At autopsy, both sarcoidosis and immunoglobulin (Ig) lambda light-chain amyloidosis were present in the native atria, lungs, thyroid, liver, spleen, and kidneys. Sarcoid granulomas alone were present in the parathyroids, lymph nodes, and bone marrow. Amyloid deposition alone was present in the aorta, stomach, large bowel, and urinary bladder. There was no evidence of plasma cell dyscrasia, or underlying gammopathy. This unusual association was described in only two other cases in the medical literature. However, this is the first case of sarcoidosis and AL amyloidosis with successful sequencing and identification of Ig lambda light-chain amyloid, and in which there was no evidence of plasma cell dyscrasia.     

Progressive cardiac fibrosis and myocyte injury in v-fps transgenic mice. A model for primary disorders of connective tissue in the heart?

Transgenic mice that express v-fps protein-tyrosine kinase have severe cardiac or neurologic abnormalities and a high incidence of lymphoid or mesenchymal tumors. The cardiac lesions of v-fps transgenic mice were examined at less than 1, 2, 3, 6, 14, 26, and 43 weeks of age (total N = 19) and compared with nontransgenic littermate controls (N = 34). Three of eight transgenic animals 1 to 4 days old showed moderate proliferation of connective tissue elements most evident along the septal endocardium of the right ventricle. Variable cardiac hypertrophy was seen grossly in 2- to 14-week-old transgenic animals, and marked biventricular dilatation was present in those 6 to 43 weeks of age. Sections of all transgenic mice 3 weeks or older revealed characteristic lesions that consisted of cellular fibrosis in subendocardial, subepicardial, and perivascular sites, with associated proliferation of pericytes and fat cells. Atrophy, degeneration, and loss of entrapped myocytes were noted in transgenic animals as early as 2 weeks of age, but frank coagulative necrosis or myocytolysis was absent at all ages studied. Nonetheless, pleomorphic nuclei were found in occasional myocytes late in disease. Inflammatory cells were rare, as confirmed immunohistochemically (Thy-1 [pan-T], L3T4 [CD4], Lyt-2 [CD8], interleukin-2 receptor [activated lymphocyte], Mac-1 [macrophage], and B220 [pan-B]). Monoclonal immunoreactivity to the v-fps transgene product was positive predominantly in nonmyocyte cardiac constituents. Collectively, the data suggest a primary proliferative abnormality of connective tissue elements in the heart, accompanied by secondary myocyte damage.     

Cardiac troponin T mutation in familial cardiomyopathy with variable remodeling and restrictive physiology

We identified a unique family with autosomal dominant heart disease variably expressed as restrictive cardiomyopathy (RCM), hypertrophic cardiomyopathy (HCM), and dilated cardiomyopathy (DCM), and sought to identify the molecular defect that triggered divergent remodeling pathways. Polymorphic DNA markers for nine sarcomeric genes for DCM and/or HCM were tested for segregation with disease. Linkage to eight genes was excluded, but a cardiac troponin T (TNNT2) marker cosegregated with the disease phenotype. Sequencing of TNNT2 identified a heterozygous missense mutation resulting in an I79N substitution, inherited by all nine affected family members but by none of the six unaffected relatives. Mutation carriers were diagnosed with RCM (n = 2), non-obstructive HCM (n = 3), DCM (n = 2), mixed cardiomyopathy (n = 1), and mild concentric left ventricular hypertrophy (n = 1). Endomyocardial biopsy in the proband revealed non-specific fibrosis, myocyte hypertrophy, and no myofibrillar disarray. Restrictive Doppler filling patterns, atrial enlargement, and pulmonary hypertension were observed among family members regardless of cardiomyopathy subtype. Mutation of a sarcomeric protein gene can cause RCM, HCM, and DCM within the same family, underscoring the necessity of comprehensive morphological and physiological cardiac assessment in familial cardiomyopathy screening.     

Fasudil, a Rho-kinase inhibitor, protects against excessive endurance exercise training-induced cardiac hypertrophy, apoptosis and fibrosis in rats

Excessive endurance exercise training (EEET) is accompanied by cardiac remodeling, changes in ventricular function and increased heart failure risk. Fasudil, a potent Rho-kinase inhibitor, has been demonstrated to blunt cardiomyocyte hypertrophy, cardiac remodeling, and heart failure progression in pre-clinical trials and has been approved for clinical use in Japan. We examined the in vivo bioefficacy of fasudil against EEET-induced cardiac remodeling and the underlying molecular mechanisms. Male Sprague-Dawley rats were randomly divided into three groups: sedentary control (SC), EEET, and EEET with fasudil treatment (EEET-F). Rats in EEET and EEET-F groups ran on a motorized treadmill for 12?weeks. The results revealed that EEET increased myocardial hypertrophy (LV weight/tibial length), myocyte cross-sectional area, hypertrophy-related pathways (IL6/STAT3-MEK5-ERK5, calcineurin-NFATc3, p38 and JNK MAPK), hypertrophic markers (ANP/BNP), pro-apoptotic molecules (cytochrome C, cleaved caspase-3 and PARP), and fibrosis-related pathways (FGF-2-ERK1/2) and fibrosis markers (uPA, MMP-9 and -2). These pathways were then expressed lower in the EEET-F group when compared with the EEET group. The cardiac hypertrophic level, apoptotic pathway and fibrosis signaling were further inhibited in the fasudil-treated group. We systematically investigated the possible signaling pathways leading to EEET-induced cardiac hypertrophy, apoptosis and fibrosis. We also provide evidence for the novel function of fasudil in suppressing EEET-induced cardiac remodeling and impairment by multiple mechanisms, which suggests that the RhoA signaling pathway contributes to EEET-induced cardiac remodeling and dysfunction.     

Regional changes in myocyte size and number in propranolol-treated hyperthyroid rats

The effects of beta-adrenergic blockade and hyperthyroidism on cardiac myocyte structure was examined. Isolated myocytes were prepared from controls and rats treated for 10 weeks with desiccated thyroid hormone (T), propranolol, and desiccated thyroid hormone plus propranolol (TP). Cells were collected from the right and left ventricle. Cell volume was measured with a Coulter Channelyzer system. Cell length was measured directly using a phase microscope. Myocyte cross-sectional area was calculated from cell volume/length. In addition, hearts from animals in each group were perfusion-fixed and myocyte volume percent was determined morphometrically from tissue sections. The number of right and left ventricular myocytes was calculated using data from isolated cells and whole-sectioned tissue. Propranolol normalized heart rate in hyperthyroid rats. Heart weight to body weight ratios were elevated to a similar extent in both T and TP groups. Compared with controls, myocyte volume was increased (p less than 0.01) in each region of T and TP. Right ventricles had a greater degree of myocyte hypertrophy than left ventricles in both rat groups treated with thyroid hormones. Cell length was increased (p less than 0.01) in T and TP. Most of the myocyte hypertrophy, however, was due to an increase in cross-sectional area. Although volume was unchanged with propranolol treatment alone, myocytes from each region had an increase in length (p less than 0.01) and a reduction in cross-sectional area (N.S.). Myocyte number was slightly reduced in each treatment group, but changes were not statistically significant. In conclusion, thyroid hormones stimulate myocyte hypertrophy by increasing both length and cross-sectional area. Propranolol modifies myocyte dimensions in both euthyroid and hyperthyroid rats, but does not prevent thyroid hormone induced cardiac hypertrophy.     

Exercise-induced cardiac hypertrophy: a substrate for sudden death in athletes?

Cardiac hypertrophy is a general term signifying an increase in cardiac mass in response to applied stress. In mild, early hypertrophy, cardiac myocyte contractile performance may be normal or enhanced, whereas in severe hypertrophy associated with cardiac failure, myocyte contraction is reduced in amplitude and increased in duration. In contrast to the varied contractile response, the duration of electrical excitation shows similar changes in both mild and severe hypertrophy. Action potential duration in mid-myocardial and sub-epicardial layers is increased, which is associated with ventricular arrhythmias (in a similar manner to the long QT syndromes from other causes), based on afterdepolarizations and enhanced automaticity. Single-cell studies following exercise training in animal models show that exercise-induced cardiac hypertrophy displays features similar to mild, compensated hypertrophy from other causes. Developed shortening of unloaded single cells is increased or unchanged, and developed force in single myocytes is enhanced. Action potential duration is increased, apart from in the sub-endocardial layer. As with mild hypertrophy from other causes, this will be pro-arrhythmic because of altered dispersion of repolarization and enhanced automaticity. Major abnormalities of the ECG in man include frequent and complex ventricular ectopy, ST segment changes and prolongation of repolarization. In this review a case is presented for regarding exercise-induced cardiac hypertrophy as being no different from mild cardiac hypertrophy resulting from other, pathological causes. The cellular electrophysiological changes are sufficient to account for many of the abnormalities of the ECG, including high-grade ventricular ectopy. Sudden death in trained athletes who have no evidence of specific heart disease may be a direct consequence of cardiac hypertrophy and altered repolarization.     

Open lung biopsies in congenital heart disease for evaluation of pulmonary vascular disease. Predictive value with regard to corrective operability

For evaluation of pulmonary vascular disease 140 open lung biopsies were performed in 137 patients with congenital heart disease in order to decide whether the state of the lung vessels would allow corrective surgery. As far as possible follow-up was obtained in patients who underwent a cardiac repair. From the study of these biopsy specimens it appeared that medial hypertrophy of pulmonary arteries and changes in pulmonary veins should not be considered an impediment for a corrective operation as long as more advanced changes are absent. The same is true for intimal thickening due to longitudinal smooth muscle, post-thrombotic changes or cellular proliferation. Concentric-laminar intimal fibrosis forms no contra-indication as long as it is mild but, if severe, it is likely that hypertensive pulmonary vascular disease will progress in spite of cardiac repair. In the presence of fibrinoid necrosis or plexiform lesions correction of a cardiac anomaly should not be attempted. The presence of dilatation lesions is more disputable but probably, as long as they are scarce and not accompanied by fibrinoid necrosis or plexiform lesions, corrective surgery may be attempted. This becomes very dubious when they are more numerous.     

Chronic myocarditis induced by T cells reactive to a single cardiac myosin peptide: persistent inflammation, cardiac dilatation, myocardial scarring and continuous myocyte apoptosis

Recent recognition that an autoimmune myocarditis may precede, and result in, dilated cardiomyopathy has focused attention on immune mechanisms of myocardial injury. In this paper, we describe a model of chronic autoimmune myocarditis in the Lewis rat. The production of myocarditis has been previously described by this group and in brief is accomplished by a single tail vein infusion of activated T cells specific for a 17-amino acid peptide from rat cardiac myosin. In this report, animals were followed for approximately 6 months post-T-cell infusion. Hearts from animals which received cardiac myosin specific T cells all showed extensive fibrosis associated with ongoing inflammation. Apoptosis, identified by TdT-mediated dUTP nick end labelling (TUNEL), was identified as a mode of myocyte death in hearts with acute and chronic myocarditis but not in age- and sex-matched controls. Immunohistochemistry was used to characterize the immune infiltrate and adhesion molecules in hearts with chronic myocarditis and these findings were compared to hearts with acute myocarditis. We propose that this rat model of chronic myocarditis mimics human disease, since inflammation results in ventricular dilatation and myocyte hypertrophy reminiscent of dilated cardiomyopathy. This model offers potential for further investigation of immune, functional and possible therapeutic aspects of autoimmune related cardiomyopathies.     

Cardiomegaly due to iron deficiency in the rat (author's transl)

The effects of chronic iron deficiency were studied in new born rats. Hemoglobin concentrations were significantly depressed throughout the experimental period when compared with those of control animals. At third postnatal month, there was a 56% increase of absolute heart weight and a 230% increase of relative heart weight. Heart weight increased much more than myocytes dimensions. This finding may be interpreted as characteristic of a double process of hypertrophy and hyperplasia. Both cell hypertrophy and multiplication were responsible for the observed hypertrophy of the heart. Number of capillaries/mm2 was unchanged, but both mean capillary diameter and total surface of capillary wall increased progressively during the period of anemia. The adaptation to myocardial hypoxia may be, in this experiment situation, localized at the capillary level rather than at the mitochondria. At cell level, we did not note any particular modification of the ultrastructure and particularly no degenerative change. No mitochondrial lesions were found even in severe anemics (blood hemoglobin below 3.2 g/100 ml).     

Heterotopic transplantation of the failing rat heart as a model of left ventricular mechanical unloading toward recovery

The left ventricular assist device (LVAD) is usually used in patients with end-stage heart failure as a bridge to transplantation. Recently, some studies have reported functional recovery with the use of an LVAD, although the mechanisms responsible for recovery are not fully understood. We investigated the functional recovery of the infarcted, failing rat heart in response to mechanical unloading after heterotopic transplantation. Heart failure was induced in Lewis rats by ligating the left anterior descending artery. After 4 weeks, the infarcted hearts were harvested and heterotopically transplanted. The transplanted infarcted heart was removed after 2 weeks of unloading and examined for hypertrophy and fibrosis, as well as for mRNA levels encoding for brain natriuretic peptide, sarco(endo)plasmic reticulum Ca(2+)-ATPase2a (SERCA2a), and beta1- and beta2-adrenergic receptors. Normal and infarcted rats without transplantation served as control animals. The infarcted heart was hypertrophied as evidenced by an increase in heart weight and myocyte diameter. After unloading the infarcted heart for 2 weeks, there was a decrease in heart weight and myocyte diameter. However, the percentage of myocardial fibrosis increased after unloading. The mRNA expression of brain natriuretic peptide and the beta2-adrenergic receptor significantly improved after mechanical unloading. The levels of SERCA2a mRNA tended to increase after unloading. In conclusion, unloading the failing, infarcted heart can help normalize left ventricular hypertrophy and cardiac gene expression. This unloading model appears to partially mimic the conditions of hemodynamic support with an LVAD in heart failure patients and potentially offers insights into the mechanisms of functional recovery.     

Regulation of hypertrophic and apoptotic signaling pathways by reactive oxygen species in cardiac myocytes

Increasing evidence suggests that oxidative and nitrosative stress play an important role in regulation of cardiac myocyte growth and survival. The cardiovascular system is continuously exposed to both reactive oxygen species (ROS) and nitrogen species (RNS), collectively termed reactive inflammatory species (RIS), and imbalances between the enzymes that regulate their bioavailability are associated with cardiac hypertrophy and the pathogenesis of cardiomyopathies, myocardial infarction and heart failure. It is now clear that RIS act as critical regulators of cardiac myocyte hypertrophy and apoptosis through control of redox-sensitive signaling cascades, such as tyrosine kinases and phosphatases, protein kinase C, and mitogen-activated protein kinases. This review will focus on the mechanisms by which ROS/RNS modulate cardiac myocyte growth and apoptosis induced by neurohormones and cytokines, and will discuss evidence for a role in the pathophysiology of heart failure.     

Effect of ageing and malnutrition on rat myocardium

Summary The effects of ageing and starvation on the rat myocardium were studied by morphometric methods. Since cardiac muscle is a tissue with a high level of anisotropy, methods based on the concept of vertical planes were used to describe quantitative alterations in the rat myocyte both at the cellular and ultrastructural level. During starvation rapid and important changes were noted, particularly in the transverse dimension of cells and organelles. The most striking change, however, was the immediate dilatation of the myocyte T-system, reflecting an adaptive interaction between the intra- and extracellular environment. At the same time exocytosis of intracellular components into the extracellular space of the T-system was observed. The ratio of mitochondria to myofibrils decreased progressively during starvation. Such a decrease, in general, may reach a point when cellular energy supply becomes compromised. A comparison between different regions of the heart showed no differences and it can be concluded that the morphological changes during starvation are the same, and equally distributed, in both ventricles. The changes described in the aged rat heart point in the direction of a hypertrophy of the aged myocyte. This leads to a lower ratio between surface and volume which finds its representation at the subcellular level in a more spherical shape of nuclei and mitochondria. Unlike what is seen in malnutrition, the mitochondrial/myofibril ratio is higher in the older rat. From the morphological point of view, the atrophy of malnutrition and the hypertrophy of ageing are opposed, but in both there is a change in the relationship of the myocyte to its environment which directly influences the substrate exchange capacity. This tends to protect the myocyte in starvation but jeopardizes the older cell.