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PubMed1981

Development of the outflow tract and closure of the interventricular septum in the normal human heart.

The majority of congenital heart malformations in humans involve defects in the atrioventricular valves, the crest of the interventricular septum, and/or the outflow tract, but the position and timing of these structures during cardiac development is controversial. We examined all 622 staged, serially sectioned normal human embryos and fetuses in the Carnegie Embryological Collection, and obtained a statistical tabulation of the appearance of the endocardial cushion components and surrounding structures for 382 embryos in good condition between stages 9 and 23 inclusive, when the heart normally develops. Accurately scaled drawings of ventral and lateral views of the hearts of seven embryos from stage 13 through 22 were prepared from graphic reconstructions in order to visualize the relationships of the structures under consideration. We found that development of the outflow tract septum follows the apparent functional separation of both the left and right ventricles and the blood streams leaving them. Elevations of the endocardial cushion material are continuous throughout the outflow tract and develop as a consequence of the elliptical configuration imposed on the circular cross section of the outflow tract. The membranous interventricular septum is formed of cushion material in the space bounded by the outflow tract septum, interventricular septum, and the fused AV cushion and right outflow tract cushion. The results of this study are consistent with the assertion that functional separation of the aortic and pulmonary outflow tracts precedes anatomic septation, and that anatomic septation is brought about by mechanical modeling of developing myocardium and endocardial cushion material.

Gestational Age↗
PubMed2004

TBX5 mutations in non-Holt-Oram syndrome (HOS) malformed hearts.

The T-box transcription factor Tbx5 is important in mammalian cardiac development. Mutations in the human TBX5 gene cause Holt-Oram syndrome (HOS), a disorder characterized by heart and upper limb deformities. To determine the role of TBX5 in non-HOS patients with complex cardiac malformations, we analyzed 68 explanted hearts from unrelated patients with various cardiac abnormalities including atrial (ASD), ventricular (VSD) and atrioventricular septal defects (AVSD). Direct sequencing detected nine mutations in diseased cardiac tissues of patients, eight of which are novel. Six mutations would affect amino acids in the T-domain, and one (c.236C>T, p.Ala79Val) is within the recently identified nuclear localization signal (NLS1) region. Further, mutations were found in patients with ASD and AVSD, but not with VSD; and mutations were absent in normal heart tissue of same patients, thus indicating somatic origin. Our results suggest a possible role of somatically occurring TBX5 mutations in congenital heart disease. We show for the first time TBX5 mutations in non-HOS associated cardiac malformations and we identified a novel missense mutation that would impact nuclear localization of TBX5.

Abnormalities, Multiple↗
PubMed2003

Cardiac endothelial-myocardial signaling: its role in cardiac growth, contractile performance, and rhythmicity.

Experimental work during the past 15 years has demonstrated that endothelial cells in the heart play an obligatory role in regulating and maintaining cardiac function, in particular, at the endocardium and in the myocardial capillaries where endothelial cells directly interact with adjacent cardiomyocytes. The emerging field of targeted gene manipulation has led to the contention that cardiac endothelial-cardiomyocytal interaction is a prerequisite for normal cardiac development and growth. Some of the molecular mechanisms and cellular signals governing this interaction, such as neuregulin, vascular endothelial growth factor, and angiopoietin, continue to maintain phenotype and survival of cardiomyocytes in the adult heart. Cardiac endothelial cells, like vascular endothelial cells, also express and release a variety of auto- and paracrine agents, such as nitric oxide, endothelin, prostaglandin I(2), and angiotensin II, which directly influence cardiac metabolism, growth, contractile performance, and rhythmicity of the adult heart. The synthesis, secretion, and, most importantly, the activities of these endothelium-derived substances in the heart are closely linked, interrelated, and interactive. It may therefore be simplistic to try and define their properties independently from one another. Moreover, in relation specifically to the endocardial endothelium, an active transendothelial physicochemical gradient for various ions, or blood-heart barrier, has been demonstrated. Linkage of this blood-heart barrier to the various other endothelium-mediated signaling pathways or to the putative vascular endothelium-derived hyperpolarizing factors remains to be determined. At the early stages of cardiac failure, all major cardiovascular risk factors may cause cardiac endothelial activation as an adaptive response often followed by cardiac endothelial dysfunction. Because of the interdependency of all endothelial signaling pathways, activation or disturbance of any will necessarily affect the others leading to a disturbance of their normal balance, leading to further progression of cardiac failure.

Animals↗
PubMed2003

Cardiac rupture complicating acute myocardial infarction in the direct percutaneous coronary intervention reperfusion era.

BACKGROUND: Cardiac rupture, an uncommon yet catastrophic complication after acute myocardial infarction (AMI), has been studied primarily in the prethrombolytic and thrombolytic therapy eras but not in the direct percutaneous coronary intervention (d-PCI) reperfusion therapy era. The aim of this study was to delineate the incidence, potential risks, timing of occurrence, clinical features, and outcomes of cardiac rupture complicating AMI after d-PCI. METHODS AND RESULTS: Between May 1993 and July 2002, a total of 1,250 patients with AMI underwent d-PCI in our hospital. Of these 1,250 patients studied, 12 patients (0.96%) had cardiac rupture (ventricular septal defect [VSD], three patients; left ventricular [LV] free wall rupture, nine patients] after d-PCI, with a mean (+/- SD) time of occurrence of 52.3 +/- 36.2 h. Three patients with VSD had an insidious presentation, and two of these patients (66.6%) survived after surgical intervention. However, nine patients with LV free wall rupture always presented with sudden and unanticipated hemodynamic collapse. Cardiopulmonary resuscitation was uniformly unsuccessful in patients with LV free wall rupture, and all patients died as a result of this complication within minutes of its onset. The 30-day mortality rate was significantly higher in patients with cardiac rupture than in patients without this complication (83.3% vs 8.2%, respectively; p < 0.001). Univariate analysis demonstrated that the left anterior descending artery was the most likely to be totally occluded in patients who had developed cardiac rupture (100% vs 66.4%, respectively; p = 0.033). Multiple stepwise logistic regression analysis demonstrated that the most significant factors associated with cardiac rupture were advanced age, female gender, and lower body mass index (BMI; all p < 0.05), whereas early reperfusion with d-PCI was an independent determinant of preventing this complication (p < 0.0001). CONCLUSION: Compared with the prethrombolytic era, our study showed that d-PCI had a favorable impact on reducing the incidence of cardiac rupture after AMI. Old age, female gender, lower BMI, and longer time to reperfusion carried a substantially increased risk of cardiac rupture after patients experienced AMIs. Early successful d-PCI was the most powerful determinant of the avoidance of this catastrophic complication after AMI.

Age Factors↗
PubMed1979

A review of environmental characteristics and health effects of barium in public water supplies.

A comprehensive review is made of sources, occurrence, removal, health effects and water quality standard of barium in public drinking water supplies. The primary source of naturally occurring barium in drinking water results from the leaching and eroding of this metal from sedimentary rocks into the aquifers of ground water. It is a localized problem in several areas of the United States. The removal of barium from drinking water appears to be most efficiently accomplished utilizing ion exchange softening. Health effects studies are based primarily on animal experimentation. Such effects include stimulation of smooth, striated, and cardiac muscle, elevation of blood pressure, initiation of catecholamine release, rapid and preferential deposition in bone, and excretion principally in the feces. Humans over 60 years of age appear to be at high risk to developing cardiac arrhythmias following the barium enema. The current United States drinking water standard of 1.0 mg/l is based on several faulty assumptions and should be critically reevaluated.

Animals↗
PubMed2000

An atrioventricular canal domain defined by cardiac troponin I transgene expression in the embryonic myocardium.

During early cardiac development the atrial myocardium is continuous with the ventricular myocardium throughout the atrioventricular canal. The atrioventricular canal undergoes complex remodelling involving septation, formation of atrioventricular valves and insulation between atria and ventricles except at the level of the atrioventricular node. Understanding of these processes has been hampered by the lack of markers specific for this heart region. We have generated transgenic mice expressing beta-galactosidase under the control of the cardiac troponin I gene that show transgene expression mainly confined to the atrioventricular canal myocardium during early embryonic development. With further development beta-galactosidase positive cells are observed in the atrioventricular node and in the lower rim of both right and left atria, supporting the view that atrioventricular canal myocardium contributes to the atrioventricular node and is in part incorporated into the lower rim of the atria. These results identify the atrioventricular canal myocardium as a distinct transcriptional domain.

Animals↗
PubMedDate not supplied

A 57 year old man with chronic renal failure and cardiac tamponade who developed ischemic hepatitis.

Ischemic hepatitis is an infrequent entity, usually associated with low cardiac out put. We present a case of a 57 year-old man with chronic renal failure and cardiac tamponade who developed elevation of serum alanine transferase level of 5,054 U/L, aspartate transferase level of 8,747 U/L and lactate dehydrogenasa level of 15,220 U/L. The patient developed hepatic encephalopathy and hypoglycemia. Liver Doppler ultrasound was normal. He was seronegative for HBV and HCV, drugs list was scrutinized for the names of known hepatotoxins. Ischemic hepatitis was diagnosed. The hypoglycemia and encephalopathy were solved and the patient was discharged with normal transaminase levels. Ischemic hepatitis is typically preceded by hypotension, hypoxemia, or both. As one would expect, the most common cause of sustained systemic hypotension is cardiovascular disease. Liver biopsy is usually not necessary. The best treatment is support measures and correct the underlying condition.

Cardiac Tamponade↗
PubMed1990

Prognostic value of intravenous dipyridamole thallium imaging in patients with diabetes mellitus considered for renal transplantation.

Patients with diabetes and end-stage renal failure are known to have a high risk for cardiac morbidity and mortality associated with renal transplantation. The most efficient method to determine preoperative cardiac risk has not been established. To determine the effectiveness of intravenous dipyridamole thallium imaging in predicting cardiac events, 40 diabetic renal transplant candidates were studied preoperatively in a prospective trial. The study group consisted of 40 patients whose average age was 42 years (range 27 to 64); 34 (85%) were hypertensive and 21 (53%) were cigarette smokers. Cardiac history included chest pain in 6 patients and prior myocardial infarction in 3 patients. Dipyridamole thallium imaging showed reversible defects in 9 patients, fixed defects in 8 patients and normal scans in 23 patients. Dipyridamole thallium imaging was performed using 0.56 mg/kg of dipyridamole infused intravenously over 4 minutes. Cardiac events occurred only in patients with reversible thallium defects, of which there were 6. Of these 6 patients, 3 had cardiac events before transplantation and 3 had them in the early postoperative phase (within 6 weeks of surgery). Of 21 patients who underwent renal transplantation, 3 had cardiac events within 6 weeks of transplantation. The average duration of follow-up was 11 months (range 1 to 21). Thus, dipyridamole thallium imaging is an effective method of identifying renal transplant candidates likely to develop cardiac complications. Routine coronary angiography may not be necessary to screen all renal transplant candidates for coronary artery disease before surgery.

Adult↗
PubMed1994

Percutaneous transvenous mitral commissurotomy in 390 cases using the Inoue balloon catheter.

Percutaneous transvenous mitral commissurotomy using the Inoue technique was performed in 390 cases of rheumatic mitral stenosis. There were 220 (56%) females and 170 (44%) males. The age range was 9-47 years [mean +/- S.D., 26 +/- 14) and all were symptomatic (New York Heart Association (NYHA) class II in 23 (6%); class III in 280 (72%); and class IV in 87 (22%) patients]. Mitral valve area increased from 0.6 +/- 0.4 to 2 +/- 0.7 cm2, mean transmitral gradients decreased from 26 +/- 8 to 5 +/- 3 mmHg and cardiac index improved from 2.2 +/- 0.8 to 3.0 +/- 0.7 l/min/m2 (P < 0.001). There were no procedure related deaths. An increase in mitral regurgitation by one grade was observed in 40 (10%) cases, with 8 (2%) cases developing severe mitral regurgitation. Oximetry evidence of left to right atrial shunt (Qp/Qs > or = 1.5:1) was observed in 11 (3%) patients. Four (1.0%) patients developed cardiac tamponade, none had thromboembolism. Follow-up of 290 cases at 26 +/- 5 weeks showed persistent improvement in clinical (NYHA class I in 98%) and echocardiographic mitral valve area. Percutaneous transvenous mitral commissurotomy is safe, easy to perform and provides excellent clinical and hemodynamic benefit in the majority of cases.

Adult↗
PubMed2006

Prognosis and therapy approaches of cardiac cachexia.

PURPOSE OF REVIEW: This review focuses on the prognostic implications and therapeutic approaches in cardiac cachexia - a syndrome that has been recognized for a long time, although it has only received increased attention lately. RECENT FINDINGS: Cardiac cachexia is a common and serious complication of chronic heart failure and associated with very poor prognosis, yet is often recognized by the clinicians only at late stage. Approximately 15% of heart failure patients will develop cardiac cachexia, defined by a 6% non-edematous, non-voluntary weight loss over a period of 6 months. Several studies have demonstrated that cardiac cachexia is a multi-factorial disease, which involves increased neurohormonal activity and immune abnormalities, resulting in hormonal and metabolic catabolic/anabolic imbalance of the body, leading to the loss of fat and lean mass and ultimately death. So far, there are no standardized therapies available for this disease. SUMMARY: Cardiac cachexia in heart failure patients is under-recognized and there is currently no causal therapy available. Several interesting treatment options exist, however, which have emerged recently, including appetite stimulants, hormones and 'classical' drugs, such as beta-blockers and ACE inhibitors.

Cachexia↗
PubMed2004

Effects of cortisol on cardiac myocytes and on expression of cardiac genes in fetal sheep.

In 17 fetal sheep aged 129 days, the effects of large-dose infusions of cortisol (72.1 mg/day for 2-3 days) on proliferation, binucleation, and hypertrophy of cardiac myocytes, cardiac expression of angiotensinogen, angiotensin receptor subtypes 1 and 2, Glut-1, glucocorticoid and mineralocorticoid receptors, proteins of the MAPK pathways and calcineurin were studied. Cortisol levels were 8.7 +/- 2.3 nM (SE) in 8 control and 1,028 +/- 189 nM in 9 treated fetuses (P < 0.001). Cortisol had no effect on myocyte binucleation. Left ventricular free wall (LVFW) uni- and binucleated myocytes were larger in cortisol-treated fetuses (P < 0.001, P < 0.05). Cortisol-treated fetuses had higher right ventricular free wall (RVFW) and LVFW angiotensinogen (Aogen) mRNA levels (treated: 2.30 +/- 0.37, n = 8 and 2.05 +/- 0.45, n = 7 vs. control: 0.94 +/- 0.12, n = 8 and 0.67 +/- 0.09, n = 7, P < 0.02). Levels of the glucose transporter Glut-1 mRNA were lower in the LVFW of treated fetuses (0.83 +/- 0.23 vs. 1.47 +/- 0.30 in control, P < 0.05, n = 7, 8). The higher the cortisol level, the greater the Aogen mRNA level (RVFW, r = 0.61, P < 0.01, n = 16; LVFW, r = 0.83, P < 0.0003, n = 14). There were no other changes in mRNA levels nor in levels of extracellular kinase, JNK, p38, their phosphorylated forms, and calcineurin. Thus high levels of cortisol such as occur after birth do not affect fetal cardiac myocyte binucleation or number but are associated with higher levels of ventricular Aogen mRNA, lower levels of Glut-1 mRNA, and hypertrophy of LVFW myocytes. These effects could impact on postnatal cardiac development.

Angiotensinogen↗
PubMed1993

Cell-cell signaling between adult rat ventricular myocytes and cardiac microvascular endothelial cells in heterotypic primary culture.

It is unclear whether signaling between endothelial cells and muscle cells within ventricular myocardium, known to be important during cardiac development, remains physiologically relevant in the adult heart. Also, the mechanisms regulating the synthesis and activation of locally acting autacoids such as endothelins, cytokines known to have potent effects on contractile function and gene expression in cardiac myocytes, are unknown, as their cells of origin within ventricular muscle. Microvascular endothelial cells isolated from ventricular tissue of adult rats do not express endothelins constitutively. However, the appearance of preproendothelin mRNA can be increased in cardiac microvascular endothelial cells by heterotypic primary culture with adult rat ventricular myocytes. Cell-cell contact, or at least close apposition, appears to be necessary to increase preproendothelin mRNA, as medium conditioned by ventricular myocytes alone was ineffective when applied to monocultures of microvascular endothelial cells. The level of TGF beta precursor mRNA is also markedly increased in microvascular endothelial cells in coculture and precedes the appearance of endothelin precursor transcripts. In coculture, TGF beta acts as an autocrine cytokine, increasing endothelin precursor mRNA and inhibiting the rate of microvascular endothelial cell proliferation. This regulation of endothelial cell phenotype in heterotypic primary cultures suggests that dynamic, reciprocal cell-cell signaling may also be occurring between microvascular endothelium and ventricular myocytes in vivo.

Amino Acid Sequence↗
PubMed2003

Knockout of ERK5 causes multiple defects in placental and embryonic development.

BACKGROUND: ERK5 is a member of the mitogen activated protein kinase family activated by certain mitogenic or stressful stimuli in cells, but whose physiological role is largely unclear. RESULTS: To help determine the function of ERK5 we have used gene targeting to inactivate this gene in mice. Here we report that ERK5 knockout mice die at approximately E10.5. In situ hybridisation for ERK5, and its upstream activator MKK5, showed strong expression in the head and trunk of the embryo at this stage of development. Between E9.5 and E10.5, multiple developmental problems are seen in the ERK5-/- embryos, including an increase in apoptosis in the cephalic mesenchyme tissue, abnormalities in the hind gut, as well as problems in vascular remodelling, cardiac development and placental defects. CONCLUSION: Erk5 is essential for early embryonic development, and is required for normal development of the vascular system and cell survival.

Abdomen↗
PubMed2005

Antenatal course of a fetal intracranial arteriovenous fistula: a case report.

BACKGROUND: Intracranial arteriovenous fistulas (AVFs) are rare in childhood. AVFs in fetuses are very rare and usually not associated with the vein of Galen. These can be solitary or multiple and may be associated with aneurysms or AVMs. The presentation of an AVF depends on the age of the patient, site and size of the fistula, and any accompanying lesion. Neonates can present with cardiac failure and a cranial bruit, infants with cardiomegaly and cardiac failure, children with hydrocephalus, and adolescents and adults with headaches, seizures or intracranial hemorrhage. CASE: Ultrasound and Doppler flow studies revealed a large, vascular lesion in the left cerebral hemisphere that was consistent with an arteriovenous malformation or fistula. The fetus developed cardiomegaly and transient pleural effusion not hydrops. Planned cesarean section without manipulation of thefetal head was performed at 39 weeks. Embolization during the neonatal period completely ceased flow through the arteriovenous fistula. At 28 months of age the child was doing well and showed no developmental or neurologic deficits. CONCLUSION: Prenatal recognition of fistulas and malformations can result in a good outcome as long as thefetus does not develop cardiac failure. Knowledge of the presence of an extensive arteriovenous malformation orfistula prior to birth allows planned delivery and permits the parents and medical team to be prepared for treatment at a tertiary care center.

Adult↗
PubMed1984

Comparative effects of verapamil, nifedipine, and diltiazem on contractile function in the isolated immature and adult rabbit heart.

The effects of postnatal development on the systolic and diastolic responses to pharmacologic blockade of the slow inward calcium current were investigated in blood-perfused hearts isolated from immature (14-21-day-old) and adult rabbits. Isovolumic left ventricular developed pressure, resting pressure, and maximal rate of pressure development (+dP/dt) at cumulative doses of either verapamil, nifedipine, or diltiazem were determined by means of an intracavitary balloon. Myocardial contractile function in the immature heart was more sensitive to pharmacologic blockade of the slow inward calcium current than is the adult heart. Doses of verapamil, or nifedipine, that comparably reduced pretreatment developed pressure and +dP/dt were approximately 10-fold less in immature as compared to the adult heart. The dose of diltiazem which reduced developed pressure and dP/dt by 50% was 3-fold less in immature as compared to the adult heart. Verapamil and nifedipine decreased resting pressure in the adult but not in the immature heart. Conversely, diltiazem decreased resting pressure in the immature while not affecting resting pressure in adult hearts. Thus, postnatal cardiac development affects both the systolic and diastolic responses to calcium channel blockade. In addition, diltiazem appears to be qualitatively and quantitatively different from verapamil and nifedipine with respect to the age-related cardiac effects of calcium channel blockade.

Aging↗
PubMed2003

Heart development in the spotted dolphin (Stenella attenuata).

Marine mammals show many deviations from typical mammalian characteristics due to their high degree of specialization to the aquatic environment. In Cetaceans, some of the features of limbs and dentition resemble very ancestral patterns. In some species, hearts with a clearly bifid apex (a feature normally present during mammalian embryogenesis prior to completion of ventricular septation) have been described. However, there is a scant amount of data regarding heart development in Cetaceans, and it is not clear whether the bifid apex is the rule or the exception. We examined samples from a unique collection of embryonic dolphin specimens macroscopically and histologically to learn more about normal cardiac development in the spotted dolphin. It was found that during the dolphin's 280 days of gestation, the heart completes septation at about 35 days. However, substantial trabecular compaction, which normally occurs in chicks, mice, and humans at around that time period, was delayed until day 60, when coronary circulation became established. At that time, the apex still appeared bifid, similarly to early fetal mouse or rat hearts. By day 80, however, the heart gained a compacted, characteristic shape, with a single apex. It thus appears that the bifid apex in the adult Cetacean heart is probably particular to certain species, and its significance remains unclear.

Animals↗
PubMed2005

Expression and regulation of the atrial natriuretic factor encoding gene Nppa during development and disease.

The endocrine function of the heart was shown by the identification of a potent inhibitor of renal tubular NaCl reabsorbtion, atrial natriuretic peptide/factor (ANP), in atrial extracts. Since then, Nppa, the gene encoding ANP, has become an important tool for molecular and developmental biologists. Expression of Nppa is an early and specific marker for the differentiating working myocardium of the atria and ventricles of the developing heart. Around the time of birth, ventricular Nppa expression is down-regulated, to be reactivated in response to a variety of cardiovascular disorders. Many aspects of the regulatory pathways that control Nppa gene expression during cardiac development or disease have been revealed. However, several fundamental issues remain to be resolved. Particularly, the regulatory mechanisms underlying the ventricular Nppa expression in the embryonic heart and the reactivation in the failing ventricle remain unclear. Here we review current knowledge on the transcriptional regulation of the Nppa gene.

Animals↗
PubMed2002

A role for bone morphogenetic protein signaling in cardiomyocyte differentiation.

Elucidating molecular mechanisms that regulate induction of cardiomyocyte differentiation is important because it may lead to practical therapeutic application for tissue regeneration in various heart diseases. Recent studies have demonstrated that some growth factors regulate expression of cardiac transcription factors and play a pivotal role in cardiac development. This study investigated the roles of bone morphogenetic proteins (BMPs) and their downstream molecules, using P19CL6 cardiomyogenic cell lines. Several lines of evidence show that BMPs are indispensable for cardiomyocyte differentiation and induce differentiation through two cardiac transcription factors, Csx/Nkx2-5 and GATA-4. Furthermore, it was demonstrated that not only Smads and TAK1, important mediators of transforming growth factor-beta signaling, but also their common target, ATF-2 transcription factor, play a critical role in cardiomyocyte differentiation.

Animals↗