Biochemical and immunological markers of insufficiency of blood circulation in children with cardiomyopathies

Complex clinical-laboratory investigation of children with congestive heart failure developed on the basis of dilated cardiomyopathy and hypertrophic cardiomyopathy has been carried out. The development of congestive heart failure in children with cardiomyopathy was accompanied by changes in activity of creatine phosphokinase, MB isoform of creatine phosphokinase, and also blood serum lactate, neopterin, TNF-α, interleukin-2 (IL-2), interleukin-6 (IL-6), and the soluble receptors for IL-2 and IL-6 (sIL-2R, sIL-6R). The energy deficit in patients with congestive heart failure is associated with pronounced impairments of expression of neopterin, TNF-α, IL-2, IL-6 and their receptors. The role of cytokines in formation of dysregulation processes is analyzed at the level of intercellular and organ local interactions. A cascade of multiple biochemical and molecular processes including impairments of membrane integrity and ion transport, apoptosis, proteolysis followed by fibrosis of myocardium finally cause myocardial remodeling, the development, chronization and progression of congestive heart failure in children with cardiomyopathy.     

Beneficial effect of ACE inhibitor in congestive heart failure

The effects of captopril, an angiotensin-converting enzyme inhibitor, on congestive heart failure (CHF) were investigated in animal and clinical studies. Congestive heart failure was induced in rats by a combination of pressure and volume overload. Cardiac pressure overload was induced by constricting one renal artery (Goldblatt rat) and volume overload was induced by aorto-caval fistula. Captopril (100 mg/kg/day) was then administered for 14 weeks. Isometric contraction was assessed using isolated left ventricular papillary muscles. The maximum developed tension and the maximum rate of increase in tension (dT/dtmax) were decreased in untreated rats with CHF and improved in captopriltreated rats. The left ventricular myosin isoenzyme pattern was shifted towards V3 in untreated rats with CHF, and was shifted back towards V1 in the captopril-treated rats. In the clinical study, captopril (37.5–75 mg/day) was administered to patients with cardiomyopathy for 12 months. There was no effect on left ventricular mass in hypertrophic cardiomyopathy, although systolic anterior motion of the mitral valve disappeared in one patient. In dilated cardiomyopathy, however, left ventricular mass tended to decrease. These results indicate that captopril has a beneficial effect in congestive heart failure.     

Congestive cardiomyopathy in the woodchuck, Marmota monax

Congestive cardiomyopathy was diagnosed during post mortem examination in eight of 149 adult woodchucks from New York. The eight woodchucks, four males and four females, died spontaneously without clinical signs of heart failure having been detected. The primary lesion was a grossly enlarged and dilated heart. Histologic lesions consisted of multifocal myocardial degeneration and necrosis. Secondary lesions of congestive heart failure were observed.     

The therapeutic potential of stem cells in heart disease

Abstract.  Coronary heart disease and chronic heart failure are common and have an increasing frequency. Although interventional and conventional drug therapy may delay ventricular remodelling, there is no basic therapeutic regime available for preventing or even reversing this process. Chronic coronary artery disease and heart failure impairs quality of life and are associated with subsequent worsening of the cardiac pump function. Numerous studies within the past few years have been demonstrated, that the intracoronary stem cell therapy has to be considered as a safe therapeutic procedure in heart disease, when destroyed and/or compromised heart muscle must be regenerated. This kind of cell therapy with autologous bone marrow cells is completely justified ethically, except for the small numbers of patients with direct or indirect bone marrow disease (e.g. myeloma, leukaemic infiltration) in whom there would be lesions of mononuclear cells. Several preclinical as well as clinical trials have shown that transplantation of autologous bone marrow cells or precursor cells improved cardiac function after myocardial infarction and in chronic coronary heart disease. The age of infarction seems to be irrelevant to regenerative potency of stem cells, since stem cells therapy in old infarctions (many years old) is almost equally effective in comparison to previous infarcts. Further indications are non-ischemic cardiomyopathy (dilative cardiomyopathy) and heart failure due to hypertensive heart disease.     

Studies of heart disease and failure in aged female squirrel monkeys (Saimiri sp.)

Lesions consistent with heart failure were found in 23 of 88 adult squirrel monkeys that died between 1995 and 1999 at the Squirrel Monkey Breeding and Research Resource (SMBRR). This provided a rationale for a study surveying aged animals in the SMBRR for normal cardiac characteristics, using echocardiography (ECHO) and electro-cardiogram. In the pilot study, ECHO and electrocardiography were performed on 59 healthy female squirrel monkeys aged 10 years or older and 39 five-year-old monkeys. Parameters were heart rate, P-wave duration and amplitude, and PR, QRS, and QT intervals (electrocardiography), and ejection fraction. Two animals with cardiomyopathy were identified and received similar testing. Advanced-study animals had the same measurements, plus left ventricular internal diameter-systole (LVIDs) and -diastole (LVIDd), left atrial diameter-diastole (LADd) and aortic root diameter-diastole (AoRDd) by use of ECHO. Significant differences were found between groups in LADd, and P-wave and QRS interval durations. In a clinical context, these differences were not considered to be substantial. Normal aged female squirrel monkeys had significant increases in heart dimension and longer P- and QRS-wave durations than did monkeys of a five-year-old control group, although the increases were not considered clinically relevant. This study documents myocardial dynamics in healthy saimiri and those with cardiomyopathy.     

Congestive cardiomyopathy in uraemic patients on long term haemodialysis.

Five uraemic patients who developed progressive cardiac failure with clinical evidence of congestive cardiomyopathy at the start or during haemodialysis treatment were studied. The diagnosis of cardiomyopathy, for which there was no apparent cause, was confirmed by angiocardiographic and haemodynamic studies. These showed a significant increase in left ventricular end-diastolic volume over normal values obtained in 12 patients without uraemia. The mean velocity of myocardial fibre shortening was significantly decreased, as was the index of normalised rigidity. Three of the five patients presented the complete picture of the disease. The other two also had considerable ventricular dilatation and a decreased index of normalised rigidity but normal ejection fraction and only moderately decreased myocardial contractility indices. This suggests that there may be primary involvement of normalised heart muscle rigidity followed by secondary changes in myocardial contractility in uraemic patients with congestive cardiomyopathy.     

Localization of the insulin-like growth factor system in a rat model of heart failure induced by myocardial infarction.

Although cardiac effects of growth hormone (GH) and insulin-like growth factor (IGF)-I have been reported in experimental models of heart failure and in human dilated cardiomyopathy, the IGF system has not been comprehensively assessed in the failing heart. We therefore localized the IGF system in the left ventricle during congestive heart failure after myocardial infarction (MI) in the rat. The left anterior descending coronary artery was ligated in adult female Sprague-Dawley rats and hearts were examined after 6 months when congestive heart failure had developed. In situ hybridization histochemistry was used to localize mRNA for the components of the IGF system in the left ventricle of sham and congestive heart failure animals. We were able to detect changes in the spatial distribution of mRNA for IGF-I and IGF binding proteins 3, 4, 5, and 6 in the left ventricle during congestive heart failure after MI. IGF-I and the binding proteins were predominantly increased in the infarct/peri-infarct area of the left ventricle. Other components of the IGF system were indistinguishable from the low to undetectable levels in sham-operated rats. These results demonstrate that the IGF system is altered in the failing heart and suggest that the IGF system plays an important role in the response of the heart to MI and consequent failure.     

Analysis of organic acids in the hearts of patients with idiopathic cardiomyopathy by gas chromatography—mass spectrometry

Organic acids in the hearts of patients with idiopathic cardiomyopathy, obtained by biopsy, were studied using gas chromatography—mass spectrometry. The profiling of organic acids was compared among eight cases of hypertrophic cardiomyopathy, three cases of congestive cardiomyopathy, and nine cases of other heart diseases, which were regarded as controls.It was found that almost all organic acids, especially deoxyaldonic acids of 2-deoxytetronic acid, 2,3-dideoxypentonic acid, 3-deoxy-2-C-(hydroxymethyl)tetronic acid, 3-deoxyerythropentonic acid and 3-deoxy-2-C-(hydroxymethyl)erythropentonic acid, were accumulated in large amounts in the heart in congestive cardiomyopathy, while these acids were decreased in hypertrophic cardiomyopathy. It was therefore suggested that deoxyaldonic acid metabolism in the heart in congestive cardiomyopathy is quite different from that in hypertrophic cardiomyopathy.     

Role of echocardiography in diagnosis and risk stratification in heart failure with left ventricular systolic dysfunction

Congestive heart failure with preserved left ventricular systolic function has emerged as a growing epidemic medical syndrome in developed countries, which is characterized by high morbidity and mortality rates. Rapid and accurate diagnosis of this condition is essential for optimizing the therapeutic management. The diagnosis of congestive heart failure is challenging in patients presenting without obvious left ventricular systolic dysfunction and additional diagnostic information is most commonly required in this setting. Comprehensive Doppler echocardiography is the single most useful diagnostic test recommended by the ESC and ACC/AHA guidelines for assessing left ventricular ejection fraction and cardiac abnormalities in patients with suspected congestive heart failure, and non-invasively determined basal or exercise-induced pulmonary capillary hypertension is likely to become a hallmark of congestive heart failure in symptomatic patients with preserved left ventricular systolic function. The present review will focus on the current clinical applications of spectral tissue Doppler echocardiography used as a reliable noninvasive surrogate for left ventricular diastolic pressures at rest as well as during exercise in the diagnosis of heart failure with preserved left ventricular systolic function. Chronic congestive heart failure, a disease of exercise, and acute heart failure syndromes are characterized by specific pathophysiologic and diagnostic issues, and these two clinical presentations will be discussed separately.     

氧化应激研究进展及其在缺血性心肌病发病中的作用

缺血性心肌病(ischemic cardiomyopathy,ICM)是指由于长期心肌缺血导致心肌局限性或弥漫性纤维化,从而产生心脏收缩和(或)舒张功能受损,引起心脏扩大或僵硬、充血性心力衰竭、心律失常等一系列临床表现的临床综合症。大量研究表明,ICM的发病机制与氧化应激密切相关。研究和开发新的抗氧化药物,将为缺血性心肌病的防治提供新的方向和途径。     

Cardiac abnormalities in liver cirrhosis.

Cirrhosis is associated with several circulatory abnormalities. A hyperkinetic circulation characterized by increased cardiac output and decreased arterial pressure and peripheral resistance is typical. Despite this hyperkinetic circulation, some patients with alcoholic cirrhosis have subclinical cardiomyopathy with evidence of abnormal ventricular function unmasked by physiologic or pharmacologic stress. Florid congestive alcoholic cardiomyopathy develops in a small percentage, but the concurrent presence of cirrhosis seems to retard the occurrence of overt heart failure. Even nonalcoholic cirrhosis may be associated with latent cardiomyopathy, although overt heart failure is not observed. Tense ascites is associated with some cardiac compromise, and removing or mobilizing ascitic fluid by paracentesis or peritoneovenous shunting results in short-term increases in cardiac output. Cirrhosis also appears to be associated with a decreased risk of major coronary atherosclerosis and an increased risk of bacterial endocarditis. Small hemodynamically insignificant pericardial effusions may be seen in ascitic patients. The release of atrial natriuretic peptide appears to be unimpaired in cirrhosis, although the kidney may be hyporesponsive to its natriuretic effects.     

Acute cardiac failure and hepatic ischemia induced by disopyramide phosphate.

Two patients abruptly developed congestive heart failure and elevation in serum transaminase levels when given disopyramide phosphate; enzyme abnormalities and hemodynamic status corrected upon withdrawal of the drug. Both patients had underlying ischemic cardiomyopathy. Myocardial infarction, pulmonary embolism, and viral hepatitis were ruled out in both patients. One patient had a liver biopsy documenting central hepatic necrosis with congestion, consistent with hepatic ischemia and not toxic hepatitis. In the other patient, cardiac decompensation and hepatocellular enzyme elevation were reproduced on rechallenge with the drug. Disopyramide should be used with caution in patients with heart failure.     

Exenatide improves glucose homeostasis and prolongs survival in a murine model of dilated cardiomyopathy

Background

There is growing awareness of secondary insulin resistance and alterations in myocardial glucose utilization in congestive heart failure. Whether therapies that directly target these changes would be beneficial is unclear. We previously demonstrated that acute blockade of the insulin responsive facilitative glucose transporter GLUT4 precipitates acute decompensated heart failure in mice with advanced dilated cardiomyopathy. Our current objective was to determine whether pharmacologic enhancement of insulin sensitivity and myocardial glucose uptake preserves cardiac function and survival in the setting of primary heart failure.

Methodology/Principal Findings

The GLP-1 agonist exenatide was administered twice daily to a murine model of dilated cardiomyopathy (TG9) starting at 56 days of life. TG9 mice develop congestive heart failure and secondary insulin resistance in a highly predictable manner with death by 12 weeks of age. Glucose homeostasis was assessed by measuring glucose tolerance at 8 and 10 weeks and tissue 2-deoxyglucose uptake at 75 days. Exenatide treatment improved glucose tolerance, myocardial GLUT4 expression and 2-deoxyglucose uptake, cardiac contractility, and survival over control vehicle-treated TG9 mice. Phosphorylation of AMP kinase and AKT was also increased in exenatide-treated animals. Total myocardial GLUT1 levels were not different between groups. Exenatide also abrogated the detrimental effect of the GLUT4 antagonist ritonavir on survival in TG9 mice.

Conclusion/Significance

In heart failure secondary insulin resistance is maladaptive and myocardial glucose uptake is suboptimal. An incretin-based therapy, which addresses these changes, appears beneficial.     

The origin of four squirrel monkey cell lines established by karyotype analysis

The squirrel monkey is a neotropical primate genus which is widely used in biomedical research but includes individual species and subspecies that respond differently to experimental perturbations. GTG-banding patterns of chromosomes 15 and 16, which are distinct among different squirrel monkey species and subspecies, were used to determine the origin of three lung fibroblast cell lines from squirrel monkeys of unknown genetic background (DPSO 114/74, SqMkLu/68, and 7603830) and to confirm the origin of a lymphoblast cell line (GSML) recently established from Guyanese squirrel monkey. DPSO 114/74 cells are from Peruvian squirrel monkey, SqMkLu/68 cells are Bolivian squirrel monkey, and 7603830 cells are from a Peruvian/Bolivian hybrid. Chromosome analysis of GSML cells confirmed that they are from Guyanese squirrel monkey.     

Region-resolved proteomics profiling of monkey heart

Nonhuman primates (NHPs) play an indispensable role in biomedical research because of their similarities in genetics, physiological, and neurological function to humans. Proteomics profiling of monkey heart could reveal significant cardiac biomarkers and help us to gain a better understanding of the pathogenesis of heart disease. However, the proteomic study of monkey heart is relatively lacking. Here, we performed the proteomics profiling of the normal monkey heart by measuring three major anatomical regions (vessels, valves, and chambers) based on iTRAQ-coupled LC-MS/MS analysis. Over 3,200 proteins were identified and quantified from three heart tissue samples. Furthermore, multiple bioinformatics analyses such as gene ontology analysis, protein–protein interaction analysis, and gene-diseases association were used to investigate biological network of those proteins from each area. More than 60 genes in three heart regions are implicated with heart diseases such as hypertrophic cardiomyopathy, heart failure, and myocardial infarction. These genes associated with heart disease are mainly enriched in citrate cycle, amino acid degradation, and glycolysis pathway. At the anatomical level, the revelation of molecular characteristics of the healthy monkey heart would be an important starting point to investigate heart disease. As a unique resource, this study can serve as a reference map for future in-depth research on cardiac disease-related NHP model and novel biomarkers of cardiac injury.     

琥珀酸美托洛尔与美托洛尔对慢性充血性心衰患者心功能的影响

目的：探讨琥珀酸美托洛尔缓释片与美托洛尔片对慢性心力衰竭患者的心功能的影响。方法：选取慢性充血性心衰患者182例临床患者资料,排除67例不符合入选标准病例后,按照服用美托洛尔剂型（缓释片、平片）分为两组,两组均为常规利尿剂ACEI等治疗。美托洛尔组患者服用每日服用25mg-50mg的美托洛尔治疗,均分2次服用。琥珀酸美托洛尔组每日服用23．75-95mg琥珀酸美托洛尔缓释片进行治疗。评价治疗前和治疗12个月后的相关指标,包括：一日5次的平均心率（晨起前,8时,12时,16时,夜间休息前共5次平均心率）、LVDd、EF、BUN、Crea。结果：治疗12个月后,两组患者心率均下降．琥珀酸美托洛尔组与美托洛尔组相比下降更明显（64．0±5．4VS69．5±7．6,P〈0．05）、LVDd、EF、BUN、Crea等指标在两组之间没有差别。结论：慢性充血性心衰患者应用琥珀酸美托洛尔较美托洛尔平片相比可明显降低平均心率。但对于心功能肾功能的影响。琥珀酸关托洛尔较美托洛尔平片相比无明显差异。     

Circadian Rhythm of Blood Pressure and Heart Rate in Cardiopathic Patients Before and After Heart Transplantation

The aim of this study was to investigate the natural history of the circadian rhythm of blood pressure (BP) and heart rate (HR) in 10 patients with heart failure (class IV of the New York Heart Association), who underwent heart transplantation because of primary congestive cardiomyopathy. The control group was 10 age-matched clinically healthy subjects. The BP and HR monitor-ings were performed before and after transplantation. Preoperatively, analysis of variance and cosinor methods validated the occurrence of a statistically significant BP and HR circadian rhythm in cardiopathic patients. Over the 4 days after surgery, both the cosinor method and serial section analysis were unable to validate a 24-h periodicity for BP and HR in patients with heart transplants. Six months after surgery, the BP and HR circadian rhythm was not detected as well. One year after transplantation. the BP and HR circadian rhythm was statistically validated. The recovery of the BP and HR circadian rhythm 1 year after heart transplantation can be regarded as a clinical sign of a reacquired susceptibility to neurovegetative chronoregulation.     

Postnatal changes of IgG and IgM levels in squirrel monkeys (Saimiri sciureus)

Serum IgG and IgM levels were measured in domestically bred squirrel monkeys (Saimiri sciureus) ranging in age from 0 days to 42 months, as well as in adult squirrel monkeys from the wild estimated to be 60 months or older. The results indicated that the transplacental transfer of IgG occurs in the squirrel monkey but the transferability is lower in the squirrel monkey than in the cynomolgus monkey. Immune response in the squirrel monkey occurs just after birth, as shown by IgM production.     

Cell Cycle Re-Entry and Mitochondrial Defects in Myc-Mediated Hypertrophic Cardiomyopathy and Heart Failure

While considerable evidence supports the causal relationship between increases in c-Myc (Myc) and cardiomyopathy as a part of a “fetal re-expression” pattern, the functional role of Myc in mechanisms of cardiomyopathy remains unclear. To address this, we developed a bitransgenic mouse that inducibly expresses Myc under the control of the cardiomyocyte-specific MHC promoter. In adult mice the induction of Myc expression in cardiomyocytes in the heart led to the development of severe hypertrophic cardiomyopathy followed by ventricular dysfunction and ultimately death from congestive heart failure. Mechanistically, following Myc activation, cell cycle markers and other indices of DNA replication were significantly increased suggesting that cell cycle-related events might be a primary mechanism of cardiac dysfunction. Furthermore, pathological alterations at the cellular level included alterations in mitochondrial function with dysregulation of mitochondrial biogenesis and defects in electron transport chain complexes I and III. These data are consistent with the known role of Myc in several different pathways including cell cycle activation, mitochondrial proliferation, and apoptosis, and indicate that Myc activation in cardiomyocytes is an important regulator of downstream pathological sequelae. Moreover, our findings indicate that the induction of Myc in cardiomyocytes is sufficient to cause cardiomyopathy and heart failure, and that sustained induction of Myc, leading to cell cycle re-entry in adult cardiomyocytes, represents a maladaptive response for the mature heart.