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PubMed1988

Atrial natriuretic peptide distribution in fetal and failed adult human hearts.

The distributions of atrial natriuretic peptide (ANP) in human hearts during the developmental stage and in adult pathological states was examined with an antibody specific to human alpha-ANP. With immunoblotting and immunofluorescence methods, we found that a 17-kDa protein, which is a pro ANP, was expressed in human fetal ventricles, in which the numbers of myofibers containing ANP granules were more abundant in the subendocardial region than the subepicardial region. As determined by radioimmunoassay, the content of immunoreactive ANP (per milligram protein) in the developing heart was greatest in the left atrium and occurred decreasingly in the right atrium, right ventricle, and left ventricle, respectively. Because ANP content in the left ventricle declined during the progress of gestation in developing hearts and because it was very low, if ever detectable, in normal adult hearts, ventricular ANP expression appears to be developmentally regulated from the early gestational stage. However, it was reexpressed in the ventricles of patients who had suffered from severe congestive heart failure. In this situation, we found that the ventricular ANP expression was more marked in patients with dilated cardiomyopathy than in patients with severe valvular disease. Interestingly, in the ventricles of patients with dilated cardiomyopathy, ANP contents were higher in the left ventricular free wall than in the right ventricular free wall, although the left ventricular subendocardium contained more ANP than the subepicardium, showing a transmural gradient similar to that expressed in fetal ventricles. Thus, the expression of ANP in human ventricles is developmentally regulated from the early gestational stage, and even adult ventricular myofibers can synthesize ANP during severe congestive heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Prevention of heart disease by subcutaneous desferrioxamine in patients with thalassaemia major.

BACKGROUND: Cardiac siderosis from transfused iron remains the major cause of death in thalassaemia major, despite iron chelation therapy with desferrioxamine. AIMS: Our aim was to determine the nature and extent of cardiac involvement and its relationship to desferrioxamine use in a group with thalassaemia major. METHODS: We reviewed 76 patients with thalassaemia major and performed multiple logistic regression to analyse factors affecting cardiac involvement. Factors studied included: patient sex, age, haemoglobin, serum ferritin, total transfusions, liver iron, duration of desferrioxamine use, electrocardiograms, echocardiograms and compliance to desferrioxamine treatment. RESULTS: Thirty-seven patients developed heart disease. They were older (p < 0.001), began desferrioxamine later (p < 0.001), had more liver iron (p = 0.014), higher serum ferritin levels (p = 0.023) and received more blood (p = 0.018). Compared to those with optimal compliance the odds of developing heart disease were increased 10.7 times in fair compliers (p < 0.001) and 5.1 times in poor compliers (p = 0.016). However, there was no significant difference between those with fair and poor compliance. After multivariate analysis only compliance (p = 0.02) and age at desferrioxamine onset (p = 0.004) remained significant. Compliance was inversely related to liver iron (p < 0.001), serum ferritin (p < 0.001) and age at desferrioxamine commencement (p < 0.001). CONCLUSIONS: We conclude that late commencement of desferrioxamine and noncompliance are associated with greater iron loading and an increased risk of heart disease.

Adolescent↗
PubMed2004

Reconstruction of the patterns of gene expression in the developing mouse heart reveals an architectural arrangement that facilitates the understanding of atrial malformations and arrhythmias.

Firm knowledge about the formation of the atrial components and of the variations seen in congenital cardiac malformations and abnormal atrial rhythms is fundamental to our understanding of the normal structure of the definitive atrial chambers. The atrial region is relatively inaccessible and has continued to be the source of disagreement. Seeking to resolve these controversies, we made three-dimensional reconstructions of the myocardial components of the developing atrium, identifying domains on the basis of differential expression of myocardial markers, connexin40, and natriuretic precursor peptide A. These reconstructions, made from serial sections of mouse embryos, show that from the outset of atrial development, the systemic and pulmonary veins are directly connected to the atrium. Relative to the systemic junctions, however, the pulmonary venous junction appears later. Our experience shows that three-dimensional reconstructions have three advantages. First, they provide clear access to the combined morphological and molecular data, allowing clarification and verification of morphogenetic concepts for nonmorphological experts and setting the scene for further discussion. Second, they demonstrate that, from the outset, the myocardium surrounding the pulmonary veins is distinct from that clothing the systemic venoatrial junctions. Third, they reveal an anatomical and molecular continuity between the entrance of the systemic venous tributaries, the internodal atrial myocardium, and the atrioventricular region. All these regions are derived from primary myocardium, providing a molecular basis for the observed nonrandom distribution of focal right atrial tachycardias.

Animals↗
PubMed2001

Association of increased pulse pressure with the development of heart failure in SHEP. Systolic Hypertension in the Elderly (SHEP) Cooperative Research Group.

The aim of this study was to assess the relationship between pulse pressure (PP) and the occurrence of heart failure (HF) in older persons with isolated systolic hypertension. Data from a prospective, multicenter, randomized, double-blind, placebo-controlled clinical trial were analyzed. A total of 4736 persons aged > or = 60 years with systolic blood pressure (SBP) between 160 and 219 mm Hg and diastolic blood pressure (DBP) < 90 mm Hg who participated in the Systolic Hypertension in the Elderly Program (SHEP) were studied. The main outcome measures were fatal and nonfatal HF. During 4.5 years average follow-up, fatal or nonfatal HF occurred in 160 of 4736 patients. The SBP, PP, and mean arterial pressure (MAP) were strong predictors of the development of HF (P < .0002). Cox proportional hazards regression using time-dependent covariates and controlling for MAP indicated that HF was inversely related to DBP (P = 0.002) and was directly related to pulse pressure (P = 0.002). Data were similar when patients who developed myocardial infarction during follow up were excluded. These data indicate that, in older persons with isolated systolic hypertension, high pulse pressure is associated with increased risk of heart failure independently of MAP and of the occurrence of acute myocardial infarction during follow-up.

Aged↗
PubMed2002

Partial left ventriculectomy in pediatric end-stage dilated cardiomyopathy.

OBJECTIVE: Although a recent survey on pediatric cardiomyopathy in Japan showed that 48% of patients died despite the medical treatment, pediatric cardiac transplantation is not legal in Japan. We determined the feasibility of partial left ventriculectomy as an alternative to end-stage dilated cardiomyopathy. METHOD: We retrospective analyzed partial left ventriculectomy in 4 pediatric patients with end-stage dilated cardiomyopathy. RESULTS: In case 1, an 8-month-old girl underwent semiemergency partial left ventriculectomy. Her ejection fraction increased from 10% to 25%, and her condition improved initially, but she developed heart failure and underwent cardiac transplantation 6 months later in the US. In case 2, a 3-year-old boy developed severe heart failure 2 months after ventricular septal defect repair. Intensive medical therapy failed, so partial left ventriculectomy was done, which increased his ejection fraction from 15% to 35%. His condition is stable 35 months after surgery. In case 3, a 2-year-old girl with a chromosomal anomaly undergoing ventricular septal defect repair developed progressive heart failure 1 year later. Despite emergency partial left ventriculectomy, she died of hemoptysis 2 weeks postoperatively. In case 4, a 2-year-old girl developing progressive heart failure unresponsive to medical therapy after 10 months underwent elective partial left ventriculectomy and remains in stable condition 18 months postoperatively. CONCLUSION: Partial left ventriculectomy is appropriate for selected patients with end-stage dilated cardiomyopathy if medical therapy is not effective and heart transplantation is not possible.

Cardiac Surgical Procedures↗
PubMed2003

Postnatal increase in insulin-sensitive glucose transporter expression is associated with improved recovery of postischemic myocardial function.

OBJECTIVE: Glucose is an important substrate for energy production in the developing heart. Increased glucose uptake rate and metabolism during ischemia and reperfusion are closely linked to postischemic myocardial recovery. The initial rate-limiting step for glycolysis is the transport of glucose across the plasma membrane by glucose transporters (GLUT-1 and GLUT-4). We hypothesized that changes in GLUT-1 and GLUT-4 expression in developing hearts lead to age-dependent adaptive changes in glucose uptake capacity and influence tolerance to ischemia. METHODS: Western-immunoblotting was performed to determine GLUT-1 and GLUT-4 expression in myocardial tissue from 1, 2, and 3-week-old and adult rabbits. Glucose uptake rate was measured with (31)P-nuclear magnetic resonance spectroscopy using 2-deoxyglucose as substrate in isolated perfused hearts. Hearts from same age rabbits were perfused in the Langendorff mode with crystalloid buffer or buffer plus a GLUT-4 specific antibody in order to determine GLUT-4 mediated effects on myocardial protection. The hearts were subjected to 30 minutes of normothermic ischemia followed by reperfusion. Cardiac contractile function measurements were obtained pre- and postischemia. Tissue lactate accumulation was measured in all groups at end-ischemia CONCLUSIONS: Insulin-regulated glucose transporter (GLUT-4) expression in the heart increased gradually after birth reaching nearly adult levels by 3 weeks of age. Corresponding with the higher amount of GLUT-4 protein, improved recovery of postischemic contractile function was seen in older hearts in association with increased anaerobic glycolytic capacity. Interventions to accelerate postnatal GLUT-4 expression may improve ischemic tolerance in the neonatal heart.

Age Factors↗
PubMed1997

Altered vascular function in early stages of heart failure in hamsters.

BACKGROUND: Congestive heart failure is a clinical condition associated with alterations in the normal balance of neurohumoral agents and factors acting on the vascular wall. The etiology of this condition, however, remains largely undefined. To help elucidate the pathophysiology of this disease, vascular function and angiotensin-converting enzyme activity were evaluated in 2-month-old Syrian cardiomyopathic hamsters (SCHs) that had not yet developed heart failure. Age-matched normal hamsters were used as control hamsters. METHODS AND RESULTS: Vascular function studies included determinations of contractile responses of aortic rings to 0.1 microM angiotensin II and 0.1 microM norepinephrine. In addition, endothelial function was evaluated by the vasorelaxant action of acetylcholine on norepinephrine-precontracted aortic rings. The results indicate that the pressor effect of angiotensin II (0.1 microM) was 35% greater in aortic rings from SCRs than that observed in control animals. This effect is specific for angiotensin II because the contraction induced by NE (0.1 microM) was similar in both of these strains. Angiotensin-converting enzyme activity was three-fold higher in aorta homogenates from SCHs but normal in plasma and heart tissue when compared with control hamsters. Aortic ring preparations from SCHs also exhibited endothelial dysfunction because the maximal relaxation elicited by 10 microM acetylcholine was reduced 53%. Concentration-response curves with acetylcholine yielded EC50 values that were threefold lower in SCHs (97.2 +/- 0.1 nM) than in control animals (286 +/- 7 nM). Indomethacin (1 microM) increased the vasorelaxant effect of acetylcholine 28% in SCHs and shifted to the left the concentration-response curve of this agonist, suggesting an increased relaxation with the cyclooxygenase inhibitor. No effect of indomethacin on acetylcholine-induced relaxation was observed in control animals. Sodium nitroprusside induced similar relaxations in both control animals and SCHs, suggesting that the vascular smooth muscle response is normal in SCR. CONCLUSIONS: Altogether these results point to a state of enhanced vascular contractility in young SCHs that could predispose these animals to develop heart failure, the enhanced vascular contractility could result from increased activity of the local renin-angiotensin system, augmented vascular response to angiotensin II, reduced nitric oxide synthesis, and enhanced production of prostaglandins.

Animals↗
PubMed2004

Cooperative activation of atrial naturetic peptide promoter by dHAND and MEF2C.

An intricate array of cell-specific multiprotein complexes participate in programs of cell-specific gene expression through combinatorial interaction with different transcription factors and cofactors. The dHAND basic helix-loop-helix (bHLH) transcription factor, which is essential for heart development and extra embryonic structures, is thought to regulate cardiomyocyte-specific gene expression through combinatorial interactions with other cardiac-restricted transcription factors such as GATA4 and NKX2.5. Here, we determine that dHAND also interacts with the myocyte enhancer binding factor-2c (MEF2C) protein, which belongs to MADS-box transcription factors and is essential for heart development. dHAND and MEF2C synergistically activated expression of the atrial naturetic peptide gene (ANP) in transfected HeLa cells. GST-pulldown and immunoprecipitation assay demonstrate that full-length MEF2C protein is able to interact with dHAND in vitro and in vivo, just like MEF2A and bHLH transcription factors MyoD in skeletal muscle cells. In addition, electrophoretic mobility shift assays (EMSAs) demonstrate that MEF2C and dHAND do not influence each other's DNA binding activity. Using chromatin immunoprecipitation (ChIP) analysis in H9c2 cells we show that dHAND interact with MEF2C to form protein complex and bind A/T sequence in promoter of ANP. Taken together with previous observations, these results suggest the existence of large multiprotein transcriptional complex with core DNA binding proteins that physically interact with other transcriptional factors to form favorable conformation to potentiate transcription.

Atrial Natriuretic Factor↗
PubMed2026

Hypoxia-activated scleraxis a mediates epicardial progenitor differentiation into a unique cardiac perivascular cell type.

The epicardium provides progenitor cells and paracrine signals essential for heart development and regeneration, yet the mechanisms regulating epicardial cell fate remain poorly understood. Here, we identify the transcription factor Scleraxis a (scxa) as a key regulator of epicardial progenitor differentiation in zebrafish. Single-cell transcriptomics, genetic lineage tracing, and cardiac injury models reveal transient scxa expression in activated epicardial progenitor cells (aEPCs) during developmental coronary angiogenesis and heart regeneration. scxa+ epicardial cells predominantly differentiate into a previously uncharacterized col18a1a+ perivascular population, termed epicardial-derived perivascular mesenchymal cells (Epi-PMCs), which is distinct from pericytes, vascular smooth muscle cells, and mammalian adventitial fibroblasts. Epi-PMCs closely associate with coronary vessels and may contribute to vascular stabilization and remodeling, potentially through collagen XVIII. Loss of scxa increases coronary vessel density. Hypoxia and Hif signaling induce scxa expression, identifying a hypoxia-responsive mechanism that promotes epicardial differentiation toward a vascular-supportive fate during heart development and regeneration.

Animals↗
PubMed1986

Atriopeptin distribution in the developing rat heart.

The embryonic distribution of atriopeptin (atrial natriuretic factor) in the Sprague-Dawley rat heart was mapped by immunoperoxidase staining of embryonic and neonatal hearts using rabbit antiserum to atriopeptigen purified from adult rat atrium. During the period of cardiac septation (days 14 and 16), immune serum reacted strongly with myocardial cytoplasmic granules in two sites: the inner cell layer along the cephalic curvature of the atria and the trabeculae of the incompletely divided ventricles. The youngest hearts studied (gestational day 11) displayed only nonspecific diffuse peroxidase reactivity within blood cells, indistinguishable from control sections incubated with normal rabbit serum. One week following birth, intense anti-atriopeptin reactivity was widely distributed through both atria. In addition, immunoreactive cytoplasmic granules were found at several sites in the ventricular myocardium. Along the fiber tracts of the concentric layers of the ventricular walls and interventricular septum, scattered granular foci were seen between nuclei of contiguous elongated myocytes. Positive staining was also seen within the papillary muscles and trabeculae carnae, regions shown by Alcian blue/periodic acid-Schiff base staining of sister sections to be relatively rich in glycogen. These patterns of antibody reactivity suggest the coupling of early atriopeptin secretory activity with developing cardiac function.

Aging↗
PubMed1999

Extraembryonic venous obstructions lead to cardiovascular malformations and can be embryolethal.

OBJECTIVE: To expand our knowledge concerning the effect of placental blood flow on human heart development, we used an embryonic chicken model in which extraembryonic blood flow was manipulated. METHODS: First, one of the three major vitelline veins was ligated, while blood flow was visualized with Indian ink. In this way, we could study the effect of different ligation positions on intracardiac flow patterns. Secondly, these vitelline veins were ligated permanently with a microclip until cardiac septation was completed, thereafter, the hearts were morphologically evaluated. In this way, we could study the impact of the ligation position on the severity and frequency of heart malformations. On combining the results, we were able to study the effect of different intracardiac flow patterns on heart development. RESULTS: Although ligation of each vein resulted in different intracardiac flow patterns, long-term ligation resulted in similar cardiovascular malformations in survivors. These consisted mainly of ventricular septum defects (VSDs), semilunar valve anomalies, and pharyngeal arch artery malformations. There was no significant difference (p > 0.05) between the ligation position and the incidence of cardiovascular malformations. However, the percentage mortality after clipping the left lateral vitelline vein was significantly higher (p < 0.05) than after ligation of either the right lateral or posterior vitelline vein. CONCLUSIONS: Early extraembryonic venous obstruction leads to altered flow patterns, which probably result in shear stress changes. In postseptation stages, these result in a spectrum of cardiovascular malformations irrespective of the ligation position. A diminished incidence of VSDs in the oldest stage was attributed to delayed closure of the interventricular foramen.

Animals↗
PubMed1995

Intracardiac blood flow patterns related to the yolk sac circulation of the chick embryo.

Intracardiac flow patterns during heart development were studied by injection of india ink into the yolk sac circulation of chick embryos at Hamburger-Hamilton stages 10 to 17. We injected india ink into a small venule or capillary, carefully preventing application of overpressure to the vascular system, and recorded the intracardiac route by video. From stage 12 onward, blood flow was laminar, and separate intracardiac currents were visualized. The yolk sac was divided into a left and a right half. Blood coursed through each half in concentric loops, ranging from the marginal sinus to the sinus venosus. This parallel array persisted within the heart. Bilateral to the embryo, two lateral regions arose that extended wedge-like within each half, resulting in six equally sized yolk sac regions at stage 16. The process of heart looping was not accompanied by a change in flow pattern. However, developmental changes of the yolk sac circulation were reflected in alteration of the intracardiac flow pattern. From stage 16 onward, the intracardiac flow pattern was no longer determined by the left- or right-hand side of the yolk sac but by bilateral anterior, lateral, and posterior regions of the yolk sac. Blood from the lateral regions of the yolk sac was preferentially distributed to the head. The results show that in preseptation stages a relatively stable flow pattern is present. We suggest that alterations in blood flow could influence the process of normal heart development.

Animals↗
PubMed2005

Comparison of postnatal development of heart rate responses to trigeminal stimulation in sleeping preterm and term infants.

Autonomic dysfunction has been regarded as a possible cause of the sudden infant death syndrome (SIDS) and it has been suggested that preterm infants, who are at a greater risk of SIDS than term infants, may have immature autonomic control. Our aim was to compare the maturation of cardiac autonomic control during sleep in preterm and term infants by examining heart rate responses to arousing and non-arousing trigeminal stimuli. Preterm infants (n = 15) and term infants (n = 24) were studied longitudinally with daytime polysomnography. Air-jet stimulation of the nares was delivered in both active sleep (AS) and quiet sleep (QS), and heart rate (HR) changes recorded for both arousal and non-arousal responses. Changes in HR (DeltaHR%) were calculated as the relative differences between baseline HR (BHR) and either MaxHR (arousal) or MinHR (non-arousal). Comparisons of HR changes between sleep states and postnatal ages were made with two-way anova for repeated measures and between groups with two-way anova. The increase in HR (DeltaHR%) was greater in term than preterm infants (P < 0.05), but only at 2-3 weeks corrected postnatal age (CPA). In preterm infants, there were no differences in BHR between sleep states, whereas in term infants, BHR was higher in AS than in QS at 2-3 weeks and 2-3 months of age. The smaller DeltaHR% to arousing stimuli in preterm infants compared with term infants at 2-3 weeks suggests that cardiac sympathetic activity in preterm infants may be lower than in term infants. This mechanism may account for the increased risk for SIDS of preterm infants.

Age Factors↗
PubMed1987

Transmural progression of morphologic changes during ischemic contracture and reperfusion in the normal and hypertrophied rat heart.

The purpose of this study was to compare the functional and morphologic changes that occur during ischemic contracture and reperfusion in the normal and hypertrophied heart. Hearts from Sprague-Dawley, spontaneously hypertensive (SHR), and normotensive Wistar-Kyoto rats were evaluated using a modified Langendorff perfusion apparatus. After obtaining control data, hearts were potassium-arrested, made ischemic, and studied at various time points. Regional coronary flow was assessed with the use of radiolabeled microspheres or Microfil dye infusion, and morphologic changes were evaluated by means of light and electron microscopy. Sarcomere length changes and qualitative morphologic changes during global ischemia demonstrate a transmural progression of ischemic damage starting at the endocardium and extending, with time, epicardially. The progression of ischemic changes in hypertrophied hearts of SHRs was similar to that of normal hearts; however, hypertrophied hearts developed ischemic contracture sooner than normal hearts. In addition, the development of contraction band change after ischemic contracture occurred only when hearts were reperfused and was related to the development of no-reflow.

Animals↗
PubMed2006

Early inflammation and risk of long-term development of heart failure and mortality in survivors of acute myocardial infarction predictive role of C-reactive protein.

OBJECTIVES: We aimed to study the relationship between C-reactive-protein (CRP), obtained within 12 to 24 h of symptoms onset, and long-term risk of death and heart failure (HF) in survivors of acute myocardial infarction (MI). BACKGROUND: A robust inflammatory response is an integral component of the response to tissue injury during MI. The magnitude of the early inflammatory response to ischemic injury might be an important determinant of long-term outcome. METHODS: We prospectively studied 1,044 patients admitted with acute MI and discharged from hospital in stable condition. RESULTS: During a median follow-up of 23 months (range, 6 to 42 months), 113 patients died and 112 developed HF. In a multivariable Cox regression model adjusting for clinical variables and predischarge ejection fraction, compared with patients in the first CRP quartile, the adjusted hazard ratios (HRs) for death progressively increased with higher quartiles of CRP (second quartile 1.4 [95% confidence interval (CI) 0.6 to 2.9]; third quartile 2.3 [95% CI 1.2 to 4.6]; fourth quartile 3.0 [95% CI 1.5 to 5.7]; for trend, p = 0.0002). Compared with patients in the first CRP quartile, the adjusted HRs for HF were: second quartile, 1.1 (95% CI 0.5 to 2.3); third quartile, 1.9 (95% CI 1.0 to 3.6); and fourth quartile, 2.1 (95% CI 1.2 to 3.9) (for trend, p = 0.005). CONCLUSIONS: C-reactive-protein is a marker of long-term development of HF and mortality in patients with acute MI and provides prognostic information beyond that provided by conventional risk factors and the degree of left ventricular systolic dysfunction.

C-Reactive Protein↗
PubMed2002

Ventricular remodeling does not accompany the development of heart failure in diabetic patients after myocardial infarction.

BACKGROUND: Diabetic patients are at increased risk for heart failure (HF) and other adverse events after myocardial infarction (MI). Left ventricular (LV) enlargement after MI is also associated with the same increased risk. We used data from the Survival and Ventricular Enlargement (SAVE) echocardiographic substudy to test the hypothesis that diabetes was associated with increased LV enlargement after MI. METHODS AND RESULTS: Four hundred twelve nondiabetic and 100 diabetic patients underwent echocardiographic assessment at baseline and 3 months, 1 year, and 2 years after MI. HF developed in 30% of diabetic and 17% of nondiabetic patients during follow-up (P<0.001). Baseline LV diastolic size, ejection fraction, and infarct segment length were similar between diabetic and nondiabetic patients. Diabetic patients demonstrated less LV enlargement between baseline and 2 years than nondiabetic patients (0.9+/-11.1 cm2 versus 3.8+/-10.9 cm2, P=0.047). In patients who developed HF, LV diastolic dilatation (10.0+/-12.4 cm2 versus 3.7+/-13.1 cm2, P=0.06) and systolic dilatation (4.6+/-11.8 versus 0.91+/-12.1, P=0.017) were greater in nondiabetic than in diabetic patients. LV dilatation between baseline and 2 years was a predictor of HF in nondiabetic patients, but not in diabetic patients, even after excluding patients with recurrent MI and adjusting for history of hypertension, prior MI, age, treatment group, and smoking. Diabetes modified the relationship between ventricular enlargement and the risk of HF (P=0.011). CONCLUSIONS: The increased incidence of HF after MI in diabetic patients is not explained by a greater propensity for LV remodeling.

Diabetes Complications↗