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The relationship between mitochondrial activity and diastolic dynsfunction in diabetic rat heart was investigated. Mitochondrial respiratory function was analyzed as calcium (Ca2+) uptake into the mitochondria. The results revealed a negative relationship between diabetic mitochondrial activity and regulation of ATP synthesis. Increased mitochondrial Ca2+ uptake resulted in the downregulation of ATP synthesis due to the stimulation of Ca2+-sensitive matrix dehydrogenases.

Cardiomyopathy, as well as hereditary muscular dystrophy, may be related to a deficiency of the glycoprotein called adhalin, which is part of the structure that links muscle cells together. Cardiomyopathy is disease of the heart muscle and adhalin is associated with the protein dystrophin, some forms of which are deficient in muscular dystrophy. A 13-year-old boy with muscular dystrophy had muscle weakness, an enlarged heart, arrythmia, and congestive heart failure received a heart transplant. Biopsies of his thigh and heart muscles showed that the muscle cell membranes were broken down. The levels of adhalin and a related structural glycoprotein were extremely low in the thigh muscle and undetectable in the heart muscle. Various causes, including mutation of the adhalin gene, may cause adhalin deficiency.

Cardiomyopathy caused by chronic supraventricular tachycardia (SVT) involves changes in the cytoskeletal architecture and an increase in specific cytoskeletal protein mRNA while total protein, actin and myosin heavy chain as well as left ventricular (LV) mass are unchanged. The symptoms of LV dilatation, neurohormonal activation and increased LV wall stress indicate the development of hypertrophy from myocardial growth but no growth is evident. It is possible these unusual changes and symptoms are from protein synthesis and degradative rate alterations while the cytoskeleton may be able to influence myocyte function modulation and contractile protein synthesis under cardiomyopathic disease conditions.

Cardiac toxicity is a potential complication of bone marrow transplantation because recipients frequently receive cardiotoxic chemotherapy and/or irradiation before transplantation. Most studies indicate that transient cardiac toxicity occurs within weeks of transplantation, but few studies have evaluated either cardiac status before or late after transplantation. Cardiac performance was assessed via cycle ergometry in 20 children and young adults before transplantation and 31 other children and young adults after transplantation. Mean survival time in the group post-transplantation was 3.9 years with a range of 11 months to 12.1 years. Left ventricular size and shortening fraction at rest were assessed via echocardiography. Data were compared to those of 70 healthy subjects from our laboratory. Patients before and after transplantation had normal oxygen consumptions and cardiac indices at rest. During exercise, however, patients treated for cancer both before and after bone marrow transplantation had reduced exercise times, reduced maximal oxygen consumptions, and reduced ventilatory anaerobic thresholds. Cardiac reserve, as judged by the response of the cardiac output during exercise, was reduced severely. There were no significant differences between the groups tested before and after transplantation. Patients who had been treated for aplastic anemia, who had received less intensive therapy before transplantation, performed significantly better than did patients treated for cancer. Despite these findings, only four patients had abnormalities by echo-cardiography. In conclusion, before transplantation patients with oncologic diagnoses had serious limitations in exercise performance, most likely as a result of the effects of the cardiotoxic therapy given as part of their conventional cancer therapy. Long-term survivors of bone marrow transplantation also had similar abnormalities. Since the same patients were not studied before and after transplantation, one cannot draw definite conclusions about the effect of the transplantation itself upon cardiac function. However, exercise testing is a sensitive, noninvasive method of assessing patients at risk for cardiac dysfunction secondary to potentially cardiotoxic agents. Pediatrics 1992;89:722-729

The left ventricle (LV) of the heart is the chamber responsible for pumping blood to the body after its return from oxygenation by the lungs; in some kinds of heart disease, the LV wall becomes abnormally thick. However, athletic training also produces changes in LV wall thickness that can be hard to distinguish from pathological alterations. In cases of sudden death of athletes, hypertrophic cardiomyopathy (thickening of LV walls and valves) is the most common probable cause, but more data are needed to determine the upper limits of normal LV changes in athletes. To this end, 947 competitive athletes in Italy were studied. The subjects, aged 13 to 49, were part of the group from which Olympic athletes were selected over a two-year period. They participated in soccer, rowing, cycling, track, and other events. Subjects underwent echocardiography (a noninvasive test) to determine LV wall thickness during diastole (the resting phase of heart action); other parameters, including LV mass, were also evaluated. Of interest was the extent of overlap between LV measurements in this group and similar measurements in people diagnosed with hypertrophic cardiomyopathy. Results showed that the LV end-diastolic dimensions (at the end of diastole) fell between 40 and 66 millimeters. The normal value in a nonathletic population is 54 millimeters or less, a level exceeded in 38 percent (363) of these athletes. Sixteen athletes had LV thickness equal to or greater than 13 millimeters (the usual cutoff point for hypertrophic cardiomyopathy). All were men; fifteen were rowers or canoeists. Most of their other cardiac dimensions also fell outside the normal range, but functional measurements (left ventricular filling with blood during diastole) were normal. Seven had abnormalities in their electrocardiograms. These 16 were particularly successful at their sports: eight had received medals. LV wall thickness among the 209 women studied was never greater than 11 millimeters. The greatest LV wall thickness, even among these athletes, was 16 millimeters, which can be taken as a normal upper limit among such a population. These data should be useful for diagnosing cardiac changes among athletes. (Consumer Summary produced by Reliance Medical Information, Inc.)

Hypertrophic cardiomyopathy and dilated cardiomyopathy are more common and better understood than restrictive cardiomyopathy. In restrictive cardiomyopathy, there is decreased muscle compliance in the heart. While other forms of restrictive heart disease exist, such as endocardial fibroelastosis or amyloid heart disease, in which amyloid deposits affect the heart muscle, these are generally not included in the category of idiopathic restrictive cardiomyopathy, as the causes of these other conditions are evident. In a survey of 801 major hospitals in Japan, a total of 14 men and 12 women, ranging in age from 5 to 63 years, were identified with restrictive cardiomyopathy. In three cases, there was a family history of hypertrophic cardiomyopathy. Within a mean follow-up of 145 months 10 patients died. While echocardiograms showed normal left ventricular thickness and contraction, all of the available pathologic specimens, whether autopsy or biopsy, showed some degree of fibrosis of the cardiac muscle. (Consumer Summary produced by Reliance Medical Information, Inc.)

The effects of hypertrophic cardiomyopathy-linked mutations A8V, E134D and D145E in cardiac troponin C on the properties of the C-domain sites are studied. The results have shown that calcium binding properties of the C-domain sites are important for the proper regulatory function of cardiac troponin C.

Using transgenesis as a paradigm, we show here that ax-adrenergic receptors ([[Alpha].sub.1]AR) play an important role in cardiac homeostasis. Cardiomyocyte-specific overexpression of the [[Alpha].sub.1]AR subtype resulted in the development of dilated cardiomyopathy and death at ~9 mo of age with typical signs of heart failure. Histological analyses showed the enlargement of all four cardiac chambers and cardiomyocyte disarray in the failing hearts. Transgenic animals showed increased left ventricular areas, as assessed by echocardiography. In addition, a progressive decrease in left ventricular systolic function was revealed. The abundance and activity of sarco(endo)plasmic reticulum [Ca.sub.2+]-ATPase (SERCA2) were reduced, and the ratio of phospholamban to SERCA2 was increased, [Alpha]-Myosin heavy chain (MHC) mRNA was less abundant in older transgenic ventricles, whereas [Beta]-MHC was induced in the failing hearts. Titin mRNA abundance was decreased at 9 mo, whereas atrial natriuretic factor mRNA was elevated at all times. This model mimics structural and functional features of idiopathic dilated cardiomyopathy. The results of this study suggest that chronic [[Alpha].sub.1]AR activity is deleterious for cardiac function. heart; transgenic mouse; ventricular dilation; sarco(endo) plasmic proteins; muscle mRNAs

Zhang, Xiaomin, Gohar Azhar, Jianyuan Chai, Pamela Sheridan, Koichiro Nagano, Thomas Brown, Jihong Yang, Konstantin Khrapko, Ana M. Borras, Joel Lawitts, Ravi P. Misra, and Jeanne Y. Wei. Cardiomyopathy in transgenic mice with cardiac-specific overexpression of serum response factor. Am J Physiol Heart Circ Physiol 280: H1782-H1792, 2001.--Serum response factor (SRF), a member of the MCM1, agamous, deficiens, SRF (MADS) family of transcriptional activators, has been implicated in the transcriptional control of a number of cardiac muscle genes, including cardiac [Alpha]-actin, skeletal [Alpha]-actin, [Alpha]-myosin heavy chain ([Alpha]-MHC), and [Beta]-MHC. To better understand the in vivo role of SRF in regulating genes responsible for maintenance of cardiac function, we sought to test the hypothesis that increased cardiac-specific SRF expression might be associated with altered cardiac morphology and function. We generated transgenic mice with cardiac-specific overexpression of the human SRF gene. The transgenic mice developed cardiomyopathy and exhibited increased heart weight-to-body weight ratio, increased heart weight, and four-chamber dilation. Histological examination revealed cardiomyocyte hypertrophy, collagen deposition, and interstitial fibrosis. SRF overexpression altered the expression of SRF-regulated genes and resulted in cardiac muscle dysfunction. Our results demonstrate that sustained overexpression of SRF, in the absence of other stimuli, is sufficient to induce cardiac change and suggest that SRF is likely to be one of the downstream effectors of the signaling pathways involved in mediating cardiac hypertrophy. muscle genes; hypertrophy; transcription; serum response element; signaling

Reiser, Peter J., Michael A. Portman, Xue-Han Ning, and Christine Schomisch Moravec. Human cardiac myosin heavy chain isoforms in fetal and failing adult atria and ventricles. Am J Physiol Heart Circ Physiol 280: H1814-H1820, 2001.--The goal of this study was to test the hypothesis that the relative amounts of the cardiac myosin heavy chain (MHC) isoforms MHC-[Alpha] and MHC-[Beta] change during development and transition to heart failure in the human myocardium. The relative amounts of MHC-[Alpha] and MHC-[Beta] in ventricular and atrial samples from fetal (gestational days 47-110) and nonfailing and failing adult hearts were determined. The majority of the fetal right and left ventricular samples contained small relative amounts of MHC-[Alpha] (mean [is less than] 5% of total MHC). There was a small significant decrease in the level of [MHC-[Alpha] in the ventricles between 7 and 12 wk of gestation. Fetal atria expressed predominantly MHC-[Alpha] (mean [is greater than] 95%), with MHC-[Beta] being detected in most samples. The majority of adult nonfailing right and left ventricular samples had detectable levels of MHC-[Alpha] ranging from 1 to 10%. Failing right and left ventricles expressed a significantly lower level of [MHC-[Alpha]. [MHC-[Alpha] comprised -90% of the total MHC in adult nonfailing left atria, whereas the relative amount of MHC-[Alpha] in the left atria of individuals with dilated or ischemic cardiomyopathy was -50%. The differences in MHC isoform composition between fetal and nonfailing adult atria and between fetal and nonfailing adult ventricles were not statistically significant. We concluded that the MHC isoform compositions of fetal human atria are the same as those of nonfailing adult atria and that the ventricular MHC isoform composition is different between adult nonfailing and failing hearts. Furthermore, the marked alteration in atrial MHC isoform composition, associated with cardiomyopathy, does not represent a regression to a pattern that is uniquely characteristic of the fetal stage. development; myocardium; dilated cardiomyopathy; ischemic cardiomyopathy

Role of heme oxygenase-carbon monoxide pathway in pathogenesis of cirrhotic cardiomyopathy in the rat. Am J Physiol Gastrointest Liver Physiol 280: G68-G74, 2001.--The enzyme heme oxygenase (HO), which exists in inducible (HO-1) and constitutive (HO-2) isoforms, degrades heme to biliverdin and CO. CO depresses cardiac contraction via cGMP. We aimed to clarify a possible role for the HO-CO pathway in the pathogenesis of cirrhotic cardiomyopathy in bile duct-ligated rats. Four weeks after bile duct ligation or sham operation, rat ventricles were examined for HO-1 and HO-2 mRNA by RT-PCR and for protein expression by Western blotting. Total HO enzyme activity and cGMP levels were also measured. The effects of a HO inhibitor, zinc protoporphyrin IX (ZnPP), on ventricular cGMP levels and isolated papillary muscle contractility were studied. We found that HO-1 mRNA transcription and protein expression were significantly augmented in cirrhotic hearts compared with shamoperated controls, whereas there was no difference in HO-2 mRNA or protein levels. Total HO activity and cGMP levels were significantly increased in cirrhotic ventricles vs. controls. In cirrhotic ventricles, treatment with ZnPP significantly decreased cGMP production and improved the blunted papillary muscle contractility, whereas it had no effect on control muscles. CO perfusion inhibited papillary muscle contractility, an effect completely blocked by methylene blue and partially blocked by ZnPP. These results indicate that activation of the HO-CO-cGMP pathway is involved in the pathogenesis of cirrhotic cardiomyopathy. heat shock protein; cardiac contractility; cirrhosis; guanylyl cyclase; guanosine 3',5'-cyclic monophosphate

Due to an oversight, a source of funding was inadvertently omitted from a recent article (Helton E, et al. Metabolic aspects of myocardial disease and a role for L-carnitine in [...]

Schotten, Ulrich, Karsten Filzmaier, Britta Borghardt, Simone Kulka, Friedrich Schoendube, Carlos Schumacher, and Peter Hanrath. Changes of [Beta]-adrenergic signaling in compensated human cardiac hypertrophy depend on the underlying disease. Am J Physiol Heart Circ Physiol 278: H2076-H2083, 2000.--In human heart failure, desensitization of the [Beta]-adrenergic signal transduction has been reported to be one of the main pathophysiological alterations. However, data on the [Beta]-adrenergic system in human compensated cardiac hypertrophy are very limited. Therefore, we studied the myocardial [Beta]-adrenergic signaling in patients suffering from hypertrophic obstructive cardiomyopathy (HOCM, n = 9) or from aortic valve stenosis (AoSt, n = 8). [Beta]-Adrenoceptor density determined by [[sup.125]I]iodocyanopindolol binding was reduced in HOCM and AoSt compared with nonhypertrophied, nonfailing myocardium (NF) of seven organ donors. In HOCM the protein expression of stimulatory G protein [Alpha]-subunit ([G.sub.s][Alpha]) measured by immunoblotting was unchanged, whereas the inhibitory G protein [Alpha]-subunit ([MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII]) was increased. In contrast, in AoSt, [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] protein was unchanged, but [G.sub.s][Alpha] protein was increased. Adenylyl cyclase stimulation by isoproterenol was reduced in HOCM but not in AoSt. Plasma catecholamine levels were normal in all patients. In conclusion, both forms of hypertrophy are associated with [Beta]-adrenoceptor downregulation but with different changes at the G protein level that occur before symptomatic heart failure due to progressive dilatation of the left ventricle develops and are not due to elevated plasma catecholamine levels. aortic valve stenosis; G proteins; hypertrophic obstructive cardiomyopathy; [Beta]-adrenoceptors; signal transduction

The vitamin A deficient (VAD) quail embryo lacks active retinoids, fails to express normally GATA-4, and develops a nonlooping heart tube morphogenetic defect that is a model for congenital cardiomyopathy. VAD quail embryos, or chick embryos depleted specifically for GATA factors, show in addition abnormal foregut development, characterized by apoptosis of the endoderm cells associated with presumptive myocardium during the process of heart tube formation. Exogenous retinoic acid or transplantation of normal chick embryo anterior endoderm is sufficient to rescue apoptosis as well as GATA-4 expression and results in normal development and heart tube morphogenesis. Normal posterior endoderm also contains retinoids but is unable to rescue the VAD defect. Our results indicate that a retinoid-dependent transcriptional program, mediated at least in part by GATA factors, is critical in presumptive foregut endoderm for normal heart tube morphogenesis. [C] 2000 Academic Press Key Words: cardiogenesis; GATA factors; chick; quail; vitamin A deficiency.

Eosinophils (a type of white blood cell) normally constitute from one to three percent of all white blood cells, but the number increases in response to allergic reactions and some infections. The association between a type of heart failure, restrictive cardiomyopathy, and increased levels of eosinophils has been known for over 50 years. Restrictive cardiomyopathy is characterized by rigidity of the ventricular walls, which prevents them from filling properly. Although many organs may be affected, heart dysfunction causes most symptoms and deaths. Differentiation between this form of cardiomyopathy and constrictive pericarditis (gradual scarring of the sac enclosing the heart) is difficult, but magnetic resonance imaging or biopsy may help establish the diagnosis. On rare occasions, it may be necessary to open the chest and observe the pericardium. Acute eosinophilic necrotizing myocarditis, another type of eosinophilic heart disease, is characterized by sudden onset, severe heart failure (of the ventricles), and high mortality. This is different from drug-related hypersensitivity myocarditis, distinguished by a history of sensitivity to drugs, rapid pulse, and sudden and unexpected death from heart failure. The high levels of eosinophils in the blood and tissues of affected patients suggests that these white blood cells lead directly to heart failure. All these disorders are considered to be part of a hypereosinophilic syndrome. Recent research has concentrated on major basic protein, a component of eosinophil granules, which is toxic in high concentrations, and some studies have suggested a relation between eosinophil-granule proteins and myocardial injury. Tissue damage and a high eosinophil count could also be caused by the same virus or allergen. Drug therapy is frequently helpful. Cardiomyopathy with high levels of eosinophils is relatively uncommon, but understanding this syndrome may help researchers to understand a more common disease, idiopathic dilated cardiomyopathy, which may be caused by a viral or toxic response. An antiinflammatory therapy, used for the hypereosinophilic heart disease, may also benefit this condition. (Consumer Summary produced by Reliance Medical Information, Inc.)