[Demonstration of catecholamines in rat heart during development].
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Animals↗
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Clinical decision support software for management of chronic heart failure: development and evaluation.
OBJECTIVE: To develop and evaluate clinical decision support software (CDSS) to aid physicians treat patients with chronic heart failure (CHF). METHODS: The CDSS was developed after discussions with a multidisciplinary panel. Evaluation was performed in three stages over a 6 month period including an editorial check, one-to-one interviews with potential users and educational meetings with general practitioners (GPs), junior doctors and medical students during which the CDSS was assessed in a cross-over design against paper guidelines. Opinions of the CDSS and the computer literacy of the participants were assessed by questionnaire. RESULTS: There were several changes to the CDSS at various stages of development and evaluation. One-to-one interviews generated extensive qualitative feedback. GPs had lower computer literacy scores than junior doctors and students (both p<0.01). There were small trends when comparing the CDSS with paper guidelines. GPs scored less well (CDSS 75% vs. 80%, p=0.41), while junior doctors and medical students appeared to improve their scores (72%-84%, p=0.32 and 66%-77%, p=0.19, respectively). Most (70%) found the CDSS more useful than the written guidelines. CONCLUSION: Development of CDSS using guidelines and expert opinion requires a multidisciplinary iterative process of feedback and software adaptation. Barriers to implementation identified include lower computer literacy among GPs, a lack of complexity within CDSS in addressing non-medical needs of patients and a reluctance among medical staff to consult guidelines during patient consultations. Improving computer skills, integrating CDSS into referral pathways and requests for investigations may be ways of enhancing use of this emerging technology.
Cardiology↗
Angiotensin-converting enzyme inhibitors in preventing remodeling and development of heart failure after acute myocardial infarction: results of the German multicenter study of the effects of captopril on cardiopulmonary exercise parameters (ECCE).
Early action of angiotensin-converting enzyme (ACE) inhibitors after myocardial infarction (MI) has been shown in large scale clinical trials to reduce mortality over the first weeks. However, the mechanisms involved are yet unclear and several trials showed a tendency toward a small, albeit unexpected, rise in cardiogenic shock or mortality. Since cardiopulmonary exercise testing (CPX) has become a "gold standard" in assessing the severity of heart failure, we studied--after finishing a pilot trial--the effect of captopril versus placebo in 208 patients who were individually titrated (titrated dose, mean 46/69 mg/day after 7 days/4 weeks, respectively) in order to preserve their blood pressure in the acute phase of myocardial infarction; we followed the development of congestive heart failure (CHF) over 4 weeks by measuring oxygen consumption. After 4 weeks, overall oxygen consumption at the anaerobic threshold (VO2-AT; 13.7 vs 13.1), maximal oxygen consumption (VO2max 19.3 vs 18.9 mL/kg per min) and exercise duration (896 vs 839 sec) showed a nonsignificant difference in favor of the captopril group. The predefined, categorized, combined endpoint of severe heart failure or death (heart failure necessitating ACE inhibition, VO2max < 10 mL/kg per min, or death) was significantly reduced in the captopril group (n = 7/104) versus placebo (n = 18/104; p = 0.03). Differences were mainly caused by fewer CHF events (delta n = 10). We conclude that ACE inhibition with individualized dose titration markedly reduces the 4-week incidence of severe heart failure or death; > 10 patients per 100 treated gained major benefits from this therapy.
Adult↗
Ultrastructure of muscle fibers and cells synthesizing DNA in lymph hearts of developing frogs and chick embryos.
The ultrastructure of striated muscle fibers and 3H-thymidine (3HTdr)-labeled cells adjacent to them in the lymph hearts of larvae of Rana temporaria, yearling frogs, and 9- to 13-day-old chick embryos was studied by use of electron-microscopic autoradiography. A comparatively high level of differentiation of lymph-heart muscle fibers was observed not only in yearling frogs but also in larvae. Myosatellites occurred in all stages of development. No mitoses were found in muscle fibers. In 9- to 13-day-old chick embryos the myofibers of lymph hearts were somewhat less differentiated than those of the larvae and yearling frogs. Differentiating sarcomeres were often seen in the sarcoplasm of myofibers of chick embryos. The analysis of the ultrastructure of 3HTdr-incorporating cells shows that 2-4 h after the single 3HTdr administration only mononucleated cells devoid of myofilaments are commonly labeled both in tadpoles and chick embryos. When fixation is postponed by 48-70 h, myonuclei frequently become labeled. Thus, the data obtained support the evidence that proliferation and differentiation processes in the developing muscle tissue of the lymph heart of both species studied are mutually exclusive, similar to the situation in differentiating vertebrate skeletal muscle.
Animals↗
Early heart failure as a cause of growth and tissue disorders in children with congenital heart disease.
Height, weight, total body fat, lean body mass, size of fat cells and total number of lipid-containing fat cells were compared in two groups of children, ages 2-6 years, with congenital heart disease. Twelve children who developed heart failure in infancy made up one group and 14 asymptomatic patients made up the other. No patient was cyanotic or had undergone surgical repair. Patients with heart failure were shorter and lighter than asymptomatic patients. Whereas both fat and lean tissues were less in the heart failure group, reduction in body fat was more important in producing underweight. Although there was no difference in the size of fat cells, the number of lipid-laden fat cells was diminished in the children who had early heart failure. Thus hypocellularity of fat cells appeared to be the major determinant of diminished body fat with heart failure. Because shortness and decreased lean tissue were associated with these adipose tissue abnormalities, it is likely that widespread changes are caused by early heart failure. As previously reported with hypoxemia, the early development of heart failure seems to produce tissue changes that handicap growth.
Adipose Tissue↗
[Calcifying myxoma of the right heart with development of thromboembolic pulmonary hypertension].
Two rare cases of calcified myxomas of the right heart (multiple myxomas of the right atrium and tricuspid valve and myxoma of the right ventricle originating from the subvalvular structures) are described. Both patients were operated, tumour and the tricuspid valve were removed and valve prosthesis was made. At necropsy changes characteristic of pulmonary hypertension resulting from the recurring thromboembolism by a tumourous tissue were found in one case.
Adult↗
Transcription factors in cardiogenesis: the combinations that unlock the mysteries of the heart.
Heart formation is one of the first signs of organogenesis within the developing embryo and this process is conserved from flies to man. Completing the genetic roadmap of the molecular mechanisms that control the cell specification and differentiation of cells that form the developing heart has been an exciting and fast-moving area of research in the fields of molecular and developmental biology. At the core of these studies is an interest in the transcription factors that are responsible for initiation of a pluripotent cell to become programmed to the cardiac lineage and the subsequent transcription factors that implement the instructions set up by the cells commitment decision. To gain a better understanding of these pathways, cardiac-expressed transcription factors have been identified, cloned, overexpressed, and mutated to try to determine function. Although results vary depending on the gene in question, it is clear that there is a striking evolutionary conservation of the cardiogenic program among species. As we move up the evolutionary ladder toward man, we encounter cases of functional redundancy and combinatorial interactions that reflect the complex networks of gene expression that orchestrate heart development. This review focuses on what is known about the transcription factors implicated in heart formation and the role they play in this intricate genetic program.
Alternative Splicing↗
Thyroid hormone controls the expression of insulin-like growth factor I receptor gene at different levels in lung and heart of developing and adult rats.
Thyroid hormone exerts profound effects on the insulin-like growth factors (IGFs)/IGF factor I receptor (IGF-IR) system through its action on the production of IGF-I peptide and IGF-binding proteins. Most of these actions are mediated by the direct control of pituitary GH gene by thyroid hormone. In this work, we have analyzed the possible effect of hypothyroidism on the expression of IGF-IR gene, both in adult and developing animals. Our results show that in the lung and heart, thyroid hormone exerts a negative effect on IGF-IR gene expression in the adult animals and during perinatal life (from day 15 onwards). This negative effect is exerted at different levels. In the heart, this regulation occurs at a pretranslational level, indicated by the fact that parallel changes in the number of membrane IGF-I receptors and IGF-IR transcripts were observed, whereas in lung, no effect of thyroid hormone was noted in the amount of IGF-IR transcripts, suggesting a translational or posttranslational control. GH does not seem to mediate T3 effects on this gene. In contrast, retinoic acid increases the expression of IGF-IR gene at a transcriptional or posttranscriptional level in adult lung and heart. Because the IGFE/ IGF-IR system is depressed in hypothyroid animals, the specific increase in the number of IGF-IRs in the lung and heart of these animals could represent a mechanism to ameliorate the negative effects of hypothyroidism on these important organs.
Aging↗
Effect of maternal ethanol administration on synaptic vesicles development in heart of rat offspring.
In rats exposed to ethanol either prenatally or both pre- and postnatally, the development of cardiac vesicular uptake of 3H-norepinephrine was nearly normal. However, the body and heart was lower than controls.
Animals↗
Thiazolidinediones in patients with diabetes mellitus and heart failure : implications of emerging data.
Individuals with diabetes mellitus have an increased risk of developing heart failure, usually as a consequence of coronary artery disease, although a specific diabetic cardiomyopathy, secondary to a microangiopathy, may also exist. The thiazolidinediones, a relatively new class of insulin-sensitizing agents used in the management of type 2 diabetes mellitus, have a number of complex metabolic actions on surrogate markers of atherogenesis, supported by the results of the recently published PROACTIVE (PROspective pioglitAzone Clinical Trial In macroVascular Events) trial. Unfortunately, the use of thiazolidinediones in individuals with diabetes mellitus and heart failure is limited because of a propensity to cause fluid retention. The underlying mechanisms of fluid retention have yet to be fully elucidated, but appear to be a dose-related class effect, exacerbated by combination therapy with insulin, and in some cases may be localized to peripheral edema. In parallel, echocardiographic studies show no significant effect of thiazolidinediones on cardiac structure or function. The design of epidemiologic studies describing an increased risk of developing heart failure in individuals with type 2 diabetes mellitus prescribed thiazolidinediones has been questioned, and a study of 'new users' of antihyperglycemic treatments found no increased risk of hospitalization for heart failure with thiazolidinedione therapy. There is also increasing evidence for the potential benefits of insulin sensitization in patients with diabetes mellitus and known heart failure, and a large observational study of over 16 000 patients with a principal discharge diagnosis of heart failure found a reduced mortality (hazard ratio [HR] 0.87; 95% CI 0.80, 0.94) in those prescribed thiazolidinediones. This benefit was offset by an increased risk of readmission with heart failure (HR 1.06; 95% CI 1.00, 1.09). Despite an increase in fluid-related events, recent studies suggest that individuals with type 2 diabetes mellitus and heart failure (New York Heart Association grade I/II) can be treated with thiazolidinediones with appropriate monitoring and adjustment of heart failure therapies. These findings would suggest the need for large-scale, prospective trials to investigate the safety and potential benefits of thiazolidinedione use in patients with diabetes mellitus and heart failure.
Diabetes Complications↗
Atrial contractile dysfunction, fibrosis, and arrhythmias in a mouse model of cardiomyopathy secondary to cardiac-specific overexpression of tumor necrosis factor-{alpha}.
Transgenic mice overexpressing the inflammatory cytokine TNF-alpha in the heart develop a progressive heart failure syndrome characterized by biventricular dilatation, decreased ejection fraction, decreased survival compared with non-transgenic littermates, and earlier pathology in males. TNF-alpha mice (TNF1.6) develop atrial arrhythmias on ambulatory telemetry monitoring that worsen with age and are more severe in males. We performed in vivo electrophysiological testing in transgenic and control mice, ex vivo optical mapping of voltage in the atria of isolated perfused TNF1.6 hearts, and in vitro studies on isolated atrial muscle and cells to study the mechanisms that lead to the spontaneous arrhythmias. Programmed stimulation induces atrial arrhythmias (n = 8/32) in TNF1.6 but not in control mice (n = 0/37), with a higher inducibility in males. In the isolated perfused hearts, programmed stimulation with single extra beats elicits reentrant atrial arrhythmias (n = 6/6) in TNF1.6 but not control hearts due to slow heterogeneous conduction of the premature beats. Lowering extracellular Ca(2+) normalizes conduction and prevents the arrhythmias. Atrial muscle and cells from TNF1.6 compared with control mice exhibit increased collagen deposition, decreased contractile function, and abnormal systolic and diastolic Ca(2+) handling. Thus abnormalities in action potential propagation and Ca(2+) handling contribute to the initiation of atrial arrhythmias in this mouse model of heart failure.
Action Potentials↗
A GATA-dependent nkx-2.5 regulatory element activates early cardiac gene expression in transgenic mice.
nkx-2.5 is one of the first genes expressed in the developing heart of early stage vertebrate embryos. Cardiac expression of nkx-2.5 is maintained throughout development and nkx-2.5 also is expressed in the developing pharyngeal arches, spleen, thyroid and tongue. Genomic sequences flanking the mouse nkx-2.5 gene were analyzed for early developmental regulatory activity in transgenic mice. Approximately 3 kb of 5' flanking sequence is sufficient to activate gene expression in the cardiac crescent as early as E7.25 and in limited regions of the developing heart at later stages. Expression also was detected in the developing spleen anlage at least 24 hours before the earliest reported spleen marker and in the pharyngeal pouches and their derivatives including the thyroid. The observed expression pattern from the -3 kb construct represents a subset of the endogenous nkx-2.5 expression pattern which is evidence for compartment-specific nkx-2.5 regulatory modules. A 505 bp regulatory element was identified that contains multiple GATA, NKE, bHLH, HMG and HOX consensus binding sites. This element is sufficient for gene activation in the cardiac crescent and in the heart outflow tract, pharynx and spleen when linked directly to lacZ or when positioned adjacent to the hsp68 promoter. Mutation of paired GATA sites within this element eliminates gene activation in the heart, pharynx and spleen primordia of transgenic embryos. The dependence of this nkx-2. 5 regulatory element on GATA sites for gene activity is evidence for a GATA-dependent regulatory mechanism controlling nkx-2.5 gene expression. The presence of consensus binding sites for other developmentally important regulatory factors within the 505 bp distal element suggests that combinatorial interactions between multiple regulatory factors are responsible for the initial activation of nkx-2.5 in the cardiac, thyroid and spleen primordia.
Animals↗
Preproenkephalin gene expression and [Met5]-enkephalin levels in the developing rat heart.
[Met5]-enkephalin, encoded by the preproenkephalin (PPE) gene, serves as a growth factor (opioid growth factor, OGF) during cardiac development in addition to its role as a neuroregulator. This study examined the ontogeny and relationship of gene and peptide expression in the mammalian heart during late embryonic, preweaning, and postweaning periods. Values for PPE mRNA of hearts in rats from embryonic day 16 (E16) to postnatal day 1 were 33 to 50% of levels found in adults. Adult values for the mature heart were comparable to those in the caudate, an area of the rat brain rich in PPE mRNA. Message gradually decreased during the first postnatal week to 10% of adult values and remained so until weaning. PPE mRNA on days 35 and 50 were three- and sevenfold, respectively, higher than at 21 days, and in adults was more than 50% greater than at day 50. Message for PPE in neonatal heart was regulated rapidly and in a sustained fashion by excess opioid agonist (OGF) or blockade of opioid-receptor interaction. [Met5]-enkephalin levels increased sevenfold between E18 and E20, and another 1.6-fold until birth. Having reached a zenith in the neonate, values for enkephalin-like peptide decreased gradually through the 2nd postnatal week, and were extremely low in adulthood. Indeed, a 43-fold difference in peptide levels was detected between neonatal and adult rat heart. These data provide evidence for the expression of a tightly regulated and distinct growth factor (OGF) during the crucial periods of cell proliferation and differentiation in the mammalian heart, and reveal that the source of OGF is autocrine and/or paracrine.
Aging↗
Identification of cardiac malformations in mice lacking Ptdsr using a novel high-throughput magnetic resonance imaging technique.
BACKGROUND: Congenital heart defects are the leading non-infectious cause of death in children. Genetic studies in the mouse have been crucial to uncover new genes and signaling pathways associated with heart development and congenital heart disease. The identification of murine models of congenital cardiac malformations in high-throughput mutagenesis screens and in gene-targeted models is hindered by the opacity of the mouse embryo. RESULTS: We developed and optimized a novel method for high-throughput multi-embryo magnetic resonance imaging (MRI). Using this approach we identified cardiac malformations in phosphatidylserine receptor (Ptdsr) deficient embryos. These included ventricular septal defects, double-outlet right ventricle, and hypoplasia of the pulmonary artery and thymus. These results indicate that Ptdsr plays a key role in cardiac development. CONCLUSIONS: Our novel multi-embryo MRI technique enables high-throughput identification of murine models for human congenital cardiopulmonary malformations at high spatial resolution. The technique can be easily adapted for mouse mutagenesis screens and, thus provides an important new tool for identifying new mouse models for human congenital heart diseases.
Animals↗
Chronic heart failure: developments and perspectives.
OBJECTIVE: To describe the clinical presentation, diagnosis, and contemporary treatment of chronic heart failure (CHF) while emphasizing the important role of the pharmacist. DATA SOURCES: English-language articles from MEDLINE pertinent to CHF. STUDY SELECTION AND DATA EXTRACTION: All relevant publications addressing CHF management were considered, including prospective comparative trials, epidemiological studies, guideline statements, review articles, and editorials. Particular focus occurred on the primary literature published after the release of noted guidelines. The Heart Failure Society of America (HFSA), and the European Society of Cardiology (ESC). DATA SYNTHESIS: Heart failure is a common disorder, especially in the elderly. To determine appropriate pharmacotherapy, one must establish the type of dysfunction (systolic versus diastolic) as well as characterize the patient's disease state according to the New York Heart Association (NYHA) functional classification system and from the American College of Cardiology (ACC)/American Heart Association (AHA), stage of diseases. Although most patients have systolic dysfunction ([ejection fraction] less than 40%), the prevalence of diastolic dysfunction (a normal to elevated ejection fraction) is rising and it accounts for at least one-third of all cases. Six drugs/drug classes are contemporary treatments in systolic heart failure, depending on NYHA functional class: angiotensin-converting-enzyme inhibitors, diuretics, beta-blockers, aldosterone antagonists, angiotensin II receptor-blockers, and digoxin. Clinicians should be aware that studies demonstrate all these drugs/drug classes prolong survival in systolic heart failure, except diuretics and digoxin. Some patients with systolic dysfunction also may be candidates for the combination of hydralazine/isosorbide dinitrate as well as nonpharmacological approaches with biventricular pacemakers and/or implantable cardioverter defibrillators. Treatment of diastolic heart failure is less evidence-based, and speculative treatments focus on control of blood pressure, tachycardia, volume overload, and myocardial ischemia. CONCLUSIONS: CHF treatment remains a therapeutic challenge. Pharmacists have an essential role in the care of these patients by avoiding drugs known to exacerbate the disease, promoting optimal pharmacotherapy, and ensuring compliance with prescribed drugs and dietary modifications.
Journal Article↗
Lower heart rate variability is associated with the development of coronary heart disease in individuals with diabetes: the atherosclerosis risk in communities (ARIC) study.
The objective of this study was to test prospectively in a population sample whether individuals with impaired heart rate variability (HRV) are at increased risk of developing coronary heart disease (CHD) and of non-CHD mortality and to test whether this relationship is more pronounced among individuals with diabetes. We examined the association between HRV and incident CHD and non-CHD mortality in a cohort of 11,654 men and women aged 45-64 years at intake, from the biracial, population-based Atherosclerosis Risk in Communities Study. Supine, resting, 2-min beat-to-beat heart rate data were collected at the baseline examination. High frequency (HF; 0.15-0.40 Hz) and low frequency (LF; 0.04-0.15 Hz) spectral powers, LF/HF ratio, normalized HF and LF, the standard deviation of all normal R-R intervals (SDNN), and the mean of the sum of the squared differences between adjacent normal R-R intervals (MSSD) were used as the conventional indexes of HRV to measure cardiac autonomic control. From this cohort, 635 cases of incident CHD (including 346 cases of incident myocardial infarction [MI] and 82 cases of fatal CHD), and 623 non-CHD deaths were identified and validated after an average of 8 years of follow-up. Among individuals with diabetes, the multivariable adjusted proportional hazards ratios (95% CI) were 2.03 (1.28-3.23), 1.60 (1.12-2.27), 1.50 (0.65-3.42), and 1.27 (0.84-1.91) for incident MI, incident CHD, fatal CHD, and non-CHD deaths, respectively, comparing the lowest quartile to the upper most three quartiles of HF. A similar pattern of associations was found for LF, SDNN, and MSSD. By contrast, there was no consistent pattern of associations among individuals without diabetes. At the population level, a lower HRV (reflective of impaired cardiac autonomic control) is statistically significantly related to the development of CHD among individuals with diabetes, independent of markers of the duration/severity of the glucose metabolism impairment. These data suggest a contribution of an impaired cardiac autonomic control to the risk of CHD among individuals with diabetes.
Autonomic Nervous System↗
Histofluorescence evaluation of sympathetic nerve fibers in hearts of developing rats exposed to ethanol during gestation.
Histofluorescence for catecholamines has been used to examine the ingrowth of the sympathetic innervation in the heart of control rats and rats exposed either pre- or perinatally to ethanol. In all groups, sympathetic innervation began in primary association with large blood vessels and, to a lesser extent, in the myocardial surface between 2 and 6 days of postnatal age. From day 9 onward, innervation progressed in density first in the atria and right ventricle. The deep muscle of the left ventricle was least innervated of all areas of the heart at all time periods examined. In pups exposed continuously to ethanol or withdrawn at birth, the innervation pattern and density were similar to controls, although slight qualitative differences may have occurred in the first two weeks of the postnatal period in the group exposed continuously to ethanol. The reported altered cardiac biochemical responses to sympathetic agents after pre- or perinatal exposure to ethanol did not appear to be associated with significant alterations in the growth of sympathetic nerve fibers into the heart. It is suggested that the alterations in the development of the cardiac sympathetic nervous system induced by ethanol probably occurs at the level of nerve terminals or adrenergic receptors.
Animals↗
Expression of connexin43 in the developing rat heart.
Connexin43 is the predominant gap junction protein expressed in the heart. To determine the relation between cardiac maturation and gap junction gene expression, the developmental profiles of connexin43 mRNA and protein were examined in the rat heart. Connexin43 mRNA levels accumulate progressively (eightfold) during embryonic and early neonatal stages, accompanied by a parallel, but temporally delayed, accumulation of connexin43 protein (15-fold). As the heart matures further, both mRNA and protein levels subsequently decline, to about 50% and 30% of their maximum levels, respectively. These observations suggest that increases in intercellular coupling that characterize cardiac development do not depend solely on modulation of connexin43 gene expression, but rather are likely to involve organization of gap junction channels into the intercalated disc.
Animals↗