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PubMed1998

Chronic amlodipine treatment during the development of heart failure.

BACKGROUND: This study examined the effects of chronic amlodipine treatment on left ventricular (LV) pump function, systemic hemodynamics, neurohormonal status, and regional blood flow distribution in an animal model of congestive heart failure (CHF) both at rest and with treadmill exercise. In an additional series of in vitro studies, LV myocyte contractile function was examined. METHODS AND RESULTS: Sixteen pigs were studied under normal control conditions and after the development of chronic pacing-induced CHF (240 bpm, 3 weeks, n=8) or chronic pacing and amlodipine (1.5 mg . kg-1 . d-1, n=8). Under ambient resting conditions, LV stroke volume (mL) was reduced with CHF compared with the normal control state (16+/-2 versus 31+/-2, P<0.05) and increased with concomitant amlodipine treatment (29+/-2, P<0.05). At rest, systemic and pulmonary vascular resistance (dyne . s-1 . cm-5) increased with CHF compared with the normal control state (3102+/-251 versus 2156+/-66 and 1066+/-140 versus 253+/-24, respectively, both P<0.05) and were reduced with amlodipine treatment (2108+/-199 and 480+/-74, respectively, P<0.05). With CHF, LV stroke volume remained reduced and was associated with a 40% reduction in myocardial blood flow during treadmill exercise, whereas chronic amlodipine treatment normalized LV stroke volume and improved myocardial blood flow. Resting and exercise-induced plasma norepinephrine levels were increased by >5-fold in the CHF group and were reduced by 50% from CHF values with chronic amlodipine treatment. Resting plasma endothelin (fmol/mL) increased with CHF compared with the normal state (10.4+/-0.9 versus 3.1+/-0.3, P<0.05) and was reduced with amlodipine treatment (6.6+/-1.1, P<0.5). With CHF, LV myocyte velocity of shortening ( microm/s) was reduced compared with normal controls (39+/-1 versus 64+/-1, P<0.05) and was increased with chronic amlodipine treatment (52+/-1, P<0.05). CONCLUSIONS: Chronic amlodipine treatment in this model of developing CHF produced favorable hemodynamic, neurohormonal, and contractile effects in the setting of developing CHF.

Amlodipine↗
PubMed2006

ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease): developed in collaboration with the Society of Cardiovascular Anesthesiologists: endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons.

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Adolescent↗
PubMed1999

Bisdiamine inhibits extracellular matrix formation and cell proliferation of atrioventricular mesenchyme from developing chick heart valves.

Abnormalities of the cushion tissues lead to atrioventricular septal defects (AVSD) and truncus arteriosus (TA). Bisdiamine exposure in the embryo frequently causes AVSD and TA in the newborn chick, mouse, or rat. We studied the effects of bisdiamine on mesenchymal cells grown in aggregate culture isolated from the developing atrioventricular valves of the stage-36 chick embryo. Fibronectin extracellular matrix formation and cell proliferation in the aggregates were assessed in various media. Chick serum stimulated the cells to produce an extracellular matrix and to divide, and the inclusion of bisdiamine inhibited both responses. If we isolated an extracellular matrix from a monolayer of mesenchymal cells and added the sonicated matrix to the medium containing serum and bisdiamine, the matrix incorporated into the aggregates and the cells entered the mitotic cycle. Our previous work established that cells need to attach to an intact extracellular matrix to begin cell division. Thus, we suggest that bisdiamine inhibits the normal formation of the extracellular matrix, leading to reduced cell proliferation, but it does not affect matrix-cell interaction. The lack of cushion growth in situ may be the cause of AVSD or TA.

Animals↗
PubMed2003

Gata factor Pannier is required to establish competence for heart progenitor formation.

Inductive signaling is of pivotal importance for developmental patterns to form. In Drosophila, the transfer of TGFbeta (Dpp) and Wnt (Wg) signaling information from the ectoderm to the underlying mesoderm induces cardiac-specific differentiation in the presence of Tinman, a mesoderm-specific homeobox transcription factor. We present evidence that the Gata transcription factor, Pannier, and its binding partner U-shaped, also a zinc-finger protein, cooperate in the process of heart development. Loss-of-function and germ layer-specific rescue experiments suggest that pannier provides an essential function in the mesoderm for initiation of cardiac-specific expression of tinman and for specification of the heart primordium. u-shaped also promotes heart development, but unlike pannier, only by maintaining tinman expression in the cardiogenic region. By contrast, pan-mesodermal overexpression of pannier ectopically expands tinman expression, whereas overexpression of u-shaped inhibits cardiogenesis. Both factors are also required for maintaining dpp expression after germ band retraction in the dorsal ectoderm. Thus, we propose that Pannier mediates as well as maintains the cardiogenic Dpp signal. In support, we find that manipulation of pannier activity in either germ layer affects cardiac specification, suggesting that its function is required in both the mesoderm and the ectoderm.

Animals↗
PubMed2006

ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing Committee to Revise the 1998 guidelines for the management of patients with valvular heart disease) developed in collaboration with the Society of Cardiovascular Anesthesiologists endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons.

Explore the source record for details and available documents.

Heart Valve Diseases↗
PubMed2003

Intracardiac fluid forces are an essential epigenetic factor for embryonic cardiogenesis.

The pattern of blood flow in the developing heart has long been proposed to play a significant role in cardiac morphogenesis. In response to flow-induced forces, cultured cardiac endothelial cells rearrange their cytoskeletal structure and change their gene expression profiles. To link such in vitro data to the intact heart, we performed quantitative in vivo analyses of intracardiac flow forces in zebrafish embryos. Using in vivo imaging, here we show the presence of high-shear, vortical flow at two key stages in the developing heart, and predict flow-induced forces much greater than might have been expected for micro-scale structures at low Reynolds numbers. To test the relevance of these shear forces in vivo, flow was occluded at either the cardiac inflow or outflow tracts, resulting in hearts with an abnormal third chamber, diminished looping and impaired valve formation. The similarity of these defects to those observed in some congenital heart diseases argues for the importance of intracardiac haemodynamics as a key epigenetic factor in embryonic cardiogenesis.

Animals↗
PubMed2002

Desmin filaments and cardiac disease: establishing causality.

BACKGROUND: Gene targeting studies indicate that desmin is not required for embryonic myogenesis and heart formation but is essential for maintaining the structural and functional integrity of myocytes. Desmin-null mouse hearts developed hypertrophy and dilatation. However, the expression of desmin is very often upregulated rather than downregulated in many cardiac diseases. Altered distribution of desmin protein has been observed in dilated cardiomyopathy, as well as desminopathies to which a number of mutations of desmin and a missense mutation of alphaB-crystallin (CryAB) have been linked. METHODS AND RESULTS: Using mouse transgenesis, we have recently demonstrated that modest overexpression of a mutant form of either desmin or CryAB in the heart leads to aberrant aggregation of desmin and CryAB proteins, disruption of the normal desmin network, perturbation of myofibril alignment, and distortion of the nuclear shape. The transgenic hearts develop concentric cardiac hypertrophy and diastolic malfunction at the early stage and ventricular dilatation and congestive heart failure subsequently. Moderate overexpression of either wild-type protein, however, did not cause discernible morphological and functional abnormalities or increased mortality. CONCLUSIONS: Thus cardiac overexpression of wild-type desmin is not detrimental whereas aberrant aggregation of desmin and disruption of the desmin network remodel the heart and compromise cardiac function.

Animals↗
PubMedDate not supplied

A newly developed porcine heart valve bioprosthesis fixed with an epoxy compound. An experimental evaluation.

Concerns with currently available bioprostheses are calcification, long-term durability, and functional and hemodynamic performance. It has been well known that these concerns are all more or less related to the fixatives, glutaraldehyde or formaldehyde, used in preserving bioprostheses. To address these concerns, we undertook the development of a porcine bioprosthesis fixed with an epoxy compound. It was discovered that the porcine leaflets fixed with the epoxy compound appeared more natural than those preserved with glutaraldehyde. The performance of this newly developed epoxy compound bioprosthesis (three samples) was evaluated in a juvenile sheep model. The results were compared to those of its glutaraldehyde counterpart (three samples). Two-dimensional echocardiographic inspection of the valvular leaflet motion indicated that the epoxy compound leaflets were more pliable than their glutaraldehyde counterparts. In addition, the epoxy compound valve appeared to open more widely than the glutaraldehyde valve. Color Doppler flow mapping demonstrated that the blood flow distal to the epoxy compound valve was slightly broader than that observed distal to the glutaraldehyde valve. Moreover, at retrieval, less calcium and pannus ingrowth were observed in the epoxy compound valve than its glutaraldehyde counterpart. The results of this preliminary evaluation indicated that the performance of this newly developed epoxy compound valve was at least equivalent to its glutaraldehyde counterpart, if not better.

Animals↗
PubMed2002

Distinct enhancers regulate skeletal and cardiac muscle-specific expression programs of the cardiac alpha-actin gene in Xenopus embryos.

During vertebrate embryonic development, cardiac and skeletal muscle originates from distinct precursor populations. Despite the profound structural and functional differences in the striated muscle tissue they eventually form, such progenitors share many features such as components of contractile apparatus. In vertebrate embryos, the alpha-cardiac actin gene encodes a major component of the myofibril in both skeletal and cardiac muscle. Here, we show that expression of Xenopus cardiac alpha-actin in the myotomes and developing heart tube of the tadpole requires distinct enhancers within its proximal promoter. Using transgenic embryos, we find that mutations in the promoter-proximal CArG box and 5 bp downstream of it specifically eliminate expression of a GFP transgene within the developing heart, while high levels of expression in somitic muscle are maintained. This sequence is insufficient on its own to limit expression solely to the myocardium, such restriction requiring multiple elements within the proximal promoter. Two additional enhancers are active in skeletal muscle of the embryo, either one of which has to interact with the proximal CArG box for correct expression to be established. Transgenic reporters containing multimerised copies of CArG box 1 faithfully detect most sites of SRF expression in the developing embryo as do equivalent reporters containing the SRF binding site from the c-fos promoter. Significantly, while these motifs possess a different A/T core within the CC(A/T)(6)GG consensus and show no similarity in flanking sequence, each can interact with a myotome-specific distal enhancer of cardiac alpha-actin promoter, to confer appropriate cardiac alpha-actin-specific regulation of transgene expression. Together, these results suggest that the role of CArG box 1 in the cardiac alpha-actin gene promoter is to act solely as a high-affinity SRF binding site.

Actins↗
PubMed1985

Heterogeneity of myosin isozyme content of rabbit heart.

A detailed study was carried out to measure the relative contents of V1 and V3 myosin isozymes in different regions of rabbit ventricle as a function of age, to assess animal-to-animal variability, and to compare different experimental approaches aimed at minimizing the effects of such variability. In addition, comparisons were made in normal developing hearts between ventricular isozyme composition and myofibrillar myosin calcium-stimulated adenosine triphosphatase. V1 isozyme predominated relative to V3 isozyme in the hearts of 2-week-old rabbits, decreasing to become a minor component in 10-week-old animals. Despite this trend, there was considerable variability in relative isozyme content of whole ventricular tissue among different rabbits of the same age. This variability was reduced in comparisons of littermates and by use of cardiac biopsies to measure changes in isozyme content in the same animal over time. Within different regions of a given heart, there also were small but significant differences in the percent V1 isozyme. The percent V1 was greatest for right ventricular papillary, followed by right ventricular free wall and then the left ventricle (free wall plus septum). There also were differences in the percent V1 within those regions, as exemplified by the significantly higher values for ventricular epicardium vs. endocardium. There was a linear correlation between the myofibrillar myosin calcium-stimulated adenosine triphosphatase and percent V1 of total isozyme for both right and left ventricles in normal and developing hearts. The regression lines for calcium-stimulated adenosine triphosphatase vs. percent V1 had a steeper slope in the left than in the right ventricle.

Aging↗
PubMed1985

Heart C-protein is transiently expressed during skeletal muscle development in the embryo, but persists in cultured myogenic cells.

The expression of cardiac and white skeletal C-protein isoforms was analyzed in developing chicken embryos and in primary skeletal muscle cell cultures by immunoblot and immunofluorescence staining using polyclonal antibodies specific for both of the two different proteins. In the embryo, cardiac C-protein was detected in the developing heart from very early stages through adulthood. In skeletal muscle, cardiac C-protein is shown to be transiently expressed between Days 3 and 15 during development. In contrast, the expression of white skeletal C-protein is gradual and progressive starting approximately from Day 15 on in development. In primary cell cultures of skeletal muscle, however, cardiac C-protein remained expressed throughout prolonged culture time, this in conjunction with white skeletal C-protein. Thus the down regulation of cardiac C-protein and the transition from cardiac C-protein to adult skeletal (white) C-protein which was observed during skeletal muscle development in vivo, does not seem to go to completion in the in vitro system.

Animals↗
PubMed2004

Ventricular but not atrial electro-mechanical delay of the embryonic heart is altered by anoxia-reoxygenation and improved by nitric oxide.

BACKGROUND/AIM: Excitation-contraction coupling is modulated by nitric oxide (NO) which otherwise has either beneficial or detrimental effects on myocardial function during hypoxia-reoxygenation. This work aimed at characterizing the variations of electromechanical delay (EMD) induced by anoxia-reoxygenation within the developing heart and determining whether atrial and ventricular EMD are modulated by NO to the same extent. METHODS: Hearts of 4 or 4.5-day-old chick embryos were excised and submitted in vitro to normoxia (45 min), anoxia (30 min) and reoxygenation (60 min). Electrocardiogram and atrial and ventricular contractions were simultaneously recorded throughout experiment. Anoxia-reoxygenation-induced chrono-, dromo-and inotropic disturbances and changes in EMD in atrium (EMDa) and ventricle (EMDv) were investigated in control hearts and in hearts exposed to 0.1, 1, 10, 50 and 100 microM of DETA-NONOate (a NO donating agent) or to 50 microM of L-NAME (a NOS inhibitor). RESULTS: Under normoxia, heart rate, PR interval, ventricular shortening velocity, EMDa and EMDv were similar in control, L-NAME-treated and DETA-NONOate-treated hearts. Under anoxia, cardiac activity became markedly erratic within less than 10 min in all groups. At the onset of reoxygenation, EMDv was increased by about 300% with respect to the preanoxic value while EMDa did not vary significatively. Compared to control conditions, L-NAME or DETA-NONOate had no influence on the negative chrono-, dromo- and inotropic effects induced by anoxia-reoxygenation. However, L-NAME prolonged EMDv during anoxia and delayed EMDv recovery during reoxygenation while 100 microM DETA-NONOate had the opposite effects. EMDa was neither affected by NOS inhibitor nor NO donor. At the end of reoxygenation, all the investigated parameters returned to their basal values. CONCLUSION: This work provides evidence that a NO-dependent pathway is involved in regulation of the ventricular excitation-contraction coupling in the anoxic-reoxygenated developing heart.

Animals↗
PubMed1998

The energy substrate switch during development of heart failure: gene regulatory mechanisms (Review).

During cardiac hypertrophy and in the failing heart, the chief myocardial energy substrate switches from fatty acids to glucose. In this review, we describe recent progress in the elucidation of the molecular regulatory events involved in the dramatic downregulation of the expression of fatty acid utilization enzymes during development of cardiac hypertrophy and failure. Much of this work has focused on the gene encoding medium-chain acyl-CoA dehydrogenase (MCAD), which catalyzes a pivotal step in the mitochondrial fatty acid -oxidation (FAO) cycle. In vivo ventricular pressure overload studies performed in mice transgenic for human MCAD promoter fragments linked to reporter genes have shown that transcription is markedly downregulated within seven days of pressure overload. The temporal pattern of this alteration in MCAD gene expression has also been characterized in a rat model of progressive pressure overload-induced left ventricular hypertrophy (LVH) and heart failure (HF) [SHHF/Mcc-facp (SHHF) rat]. MCAD mRNA levels are downregulated (>70%) during both the LVH and HF stages in the SHHF rats compared with controls. In contrast, the activity and immunodetectable levels of MCAD enzyme were not significantly reduced until the HF stage, indicating additional compensatory control at the translational or post-translational levels in the hypertrophied but non-failing ventricle. FAO enzyme expression was also shown to be downregulated in human subjects with dilated cardiomyopathy compared to age-matched controls. Taken together, these results have identified a gene regulatory program that is involved in the alterations in myocardial energy substrate utilization in the failing heart. The temporal correlation of diminished enzyme expression with onset of heart failure suggests that this alteration in lipid metabolism may play a role in the pathogenesis of pressure-overload induced heart failure. This gene regulatory pathway should be a useful target for experimental studies aimed at the molecular pathogenesis of the transition from stable cardiac hypertrophy to overt heart failure.

Acyl-CoA Dehydrogenase↗
PubMed2001

Rescuing the N-cadherin knockout by cardiac-specific expression of N- or E-cadherin.

Cell-cell adhesion mediated by some members of the cadherin family is essential for embryonic survival. The N-cadherin-null embryo dies during mid-gestation, with multiple developmental defects. We show that N-cadherin-null embryos expressing cadherins using muscle-specific promoters, alpha- or beta-myosin heavy chain, are partially rescued. Somewhat surprisingly, either N-cadherin or E-cadherin was effective in rescuing the embryos. The rescued embryos exhibited an increased number of somites, branchial arches and the presence of forelimb buds; however, in contrast, brain development was severely impaired. In rescued animals, the aberrant yolk sac morphology seen in N-cadherin-null embryos was corrected, demonstrating that this phenotype was secondary to the cardiac defect. Dye injection studies and analysis of chimeric animals that have both wild-type and N-cadherin-null cells support the conclusion that obstruction of the cardiac outflow tract represents a major defect that is likely to be the primary cause of pericardial swelling seen in null embryos. Although rescued embryos were more developed than null embryos, they were smaller than wild-type embryos, even though the integrity of the cardiovascular system appeared normal. The smaller size of rescued embryos may be due, at least in part, to increased apoptosis observed in tissues not rescued by transgene expression, indicating that N-cadherin-mediated cell adhesion provides an essential survival signal for embryonic cells. Our data provide in vivo evidence that cadherin adhesion is essential for cell survival and for normal heart development. Our data also show that E-cadherin can functionally substitute for N-cadherin during cardiogenesis, suggesting a critical role for cadherin-mediated cell-cell adhesion, but not cadherin family member-specific signaling, at the looping stage of heart development.

Animals↗
PubMed2002

Competency of embryonic cardiomyocytes to undergo Purkinje fiber differentiation is regulated by endothelin receptor expression.

Purkinje fibers of the cardiac conduction system differentiate from heart muscle cells during embryogenesis. In the avian heart, Purkinje fiber differentiation takes place along the endocardium and coronary arteries. To date, only the vascular cytokine endothelin (ET) has been demonstrated to induce embryonic cardiomyocytes to differentiate into Purkinje fibers. This ET-induced Purkinje fiber differentiation is mediated by binding of ET to its transmembrane receptors that are expressed by myocytes. Expression of ET converting enzyme 1, which produces a biologically active ET ligand, begins in cardiac endothelia, both arterial and endocardial, at initiation of conduction cell differentiation and continues throughout heart development. Yet, the ability of cardiomyocytes to convert their phenotype in response to ET declines as embryos mature. Therefore, the loss of responsiveness to the inductive signal appears not to be associated with the level of ET ligand in the heart. This study examines the role of ET receptors in this age-dependent loss of inductive responsiveness and the expression profiles of three different types of ET receptors, ET(A), ET(B) and ET(B2), in the embryonic chick heart. Whole-mount in situ hybridization analyses revealed that ET(A) was ubiquitously expressed in both ventricular and atrial myocardium during heart development, while ET(B) was predominantly expressed in the atrium and the left ventricle. ET(B2) expression was detected in valve leaflets but not in the myocardium. RNase protection assays showed that ventricular expression of ET(A) and ET(B) increased until Purkinje fiber differentiation began. Importantly, the levels of both receptor isotypes decreased after this time. Retrovirus-mediated overexpression of ET(A) in ventricular myocytes in which endogenous ET receptors had been downregulated, enhanced their responsiveness to ET, allowing them to differentiate into conduction cells. These results suggest that the developmentally regulated expression of ET receptors plays a crucial role in determining the competency of ventricular myocytes to respond to inductive ET signaling in the chick embryo.

Animals↗
PubMed2003

Nonsteroidal antiinflammatory drugs as a trigger of clinical heart failure.

BACKGROUND: Two recent studies estimated that users of nonsteroidal antiinflammatory drugs (NSAIDs) have a two-fold increase in risk of hospitalization for congestive heart failure and that this effect is larger among patients with preexisting cardiovascular diseases. METHODS: To evaluate the association between NSAID use and the risk of first-diagnosed episode of heart failure, we conducted a case-control study nested in a population-based cohort of individuals 40-84 years of age and registered in the U.K. General Practice Research Database at 1 January 1996. We excluded patients with a diagnosis of heart failure or cancer before that time and followed source members until a first-time recorded diagnosis of heart failure or cancer, or until 31 December 1996 if no disease occurred. The analysis included 857 confirmed cases and 5000 controls frequency-matched to cases by age (interval of 1 year) and sex. RESULTS: The estimated adjusted relative risk of heart failure associated with prescription of NSAIDs was 1.6 (95% confidence interval = 1.2-2.1). The relative risk was greater during the first month of therapy and was independent of treatment indication. The relative risk was 1.9 (1.3-2.8) among patients with prior history of hypertension, diabetes or renal failure and 1.3 (0.9-1.9) among individuals without these conditions. CONCLUSIONS: Initiation of NSAID therapy may double the risk of developing heart failure in susceptible individuals. Patients with renal failure, diabetes or hypertension when taking NSAIDs might be at a greater risk of developing heart failure than patients without those conditions.

Adult↗