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PubMed2001

Development of heart failure in bradycardic sick sinus syndrome.

Mounting evidence shows that elevated resting sinus rate is an independent predictor of cardiovascular morbidity and mortality in the general population, in elderly subjects, and in patients with myocardial infarction or hypertension. Therefore, a rather slow sinus rate appears to be a protecting factor acting through several mechanisms. The present contribution focuses on the relationship between sinus rate and heart failure. Its major objectives are to discuss whether in patients with heart failure a rather slow heart rate is advisable and whether a sinus bradycardia secondary to sinus node dysfunction can facilitate the development of heart failure. It has been reported that among patients with left ventricular dysfunction, increased sinus rate was a predictor of cardiovascular death at univariate analysis; however, a multivariate analysis to verify whether sinus rate was an independent predictor of mortality was not performed. Randomized trials carried out by utilizing beta-blockers or amiodarone in patients with heart failure showed that heart rate reduction by these drugs was a marker of their ability to reduce mortality. However, beta-blockers and amiodarone have additional pharmacological effects which interfere with the disease substrate. So, at present, though the results of these trials show that a rather slow sinus rate is advisable, we do not know whether in patients with heart failure sinus rate represents an independent predictor of mortality as in patients with myocardial infarction or hypertension and whether the reduction of sinus rate per se is beneficial. The results of the recent randomized THEOPACE trial showed, for the first time, that in a patient population with symptomatic sinus bradycardia (sinus rate < 50 b/min), an increase in heart rate, induced by DDD pacing or oral theophylline, reduced the incidence of overt heart failure. Therefore, sinus bradycardia seems to play a role in the genesis of heart failure. In a post-hoc analysis of the results of this trial it emerged that in the control (not treated) group, the subjects with sinus bradycardia more prone to develop heart failure were those of old age, about 80 years, with organic heart disease and severe chronotropic incompetence. However, this conclusion needs further validation.

Adult↗
PubMed2003

The Iroquois homeobox gene Irx2 is not essential for normal development of the heart and midbrain-hindbrain boundary in mice.

The Iroquois homeobox (Irx) genes have been implicated in the specification and patterning of several organs in Drosophila and several vertebrate species. Misexpression studies of chick, Xenopus, and zebra fish embryos have demonstrated that Irx genes are involved in the specification of the midbrain-hindbrain boundary. All six murine Irx genes are expressed in the developing heart, suggesting that they might possess distinct functions during heart development, and a role for Irx4 in normal heart development has been recently demonstrated by gene-targeting experiments. Here we describe the generation and phenotypic analysis of an Irx2-deficient mouse strain. By targeted insertion of a lacZ reporter gene into the Irx2 locus, we show that lacZ expression reproduces most of the endogenous Irx2 expression pattern. Despite the dynamic expression of Irx2 in the developing heart, nervous system, and other organs, Irx2-deficient mice are viable, are fertile, and appear to be normal. Although chick Irx2 has been implicated in the development of the midbrain-hindbrain region, we show that Irx2-deficient mice develop a normal midbrain-hindbrain boundary. Furthermore, Irx2-deficient mice have normal cardiac morphology and function. Functional compensation by other Irx genes might account for the absence of a phenotype in Irx2-deficient mice. Further studies of mutant mice of other Irx genes as well as compound mutant mice will be necessary to uncover the functional roles of these evolutionarily conserved transcriptional regulators in development and disease.

Animals↗
PubMed2003

Comparison of connexin expression patterns in the developing mouse heart and human foetal heart.

Heart muscle cells are electrically coupled by gap junctions, clusters of low-resistance transmembrane channels composed of connexins (Cx). The expression of the three major connexins (Cx43, Cx40 and Cx45) present in cardiac myocytes is known to be developmentally regulated but it is not clear how the patterns in the human heart compare with those found in the mouse. This issue is of importance given the wide use of transgenic mice to investigate gene function with the aim of extrapolating the results to human. In the present study we applied immunoconfocal microscopy to investigate the spatial distribution of the three connexins in the developing mouse heart and foetal human heart. Although Cx45 labelling was present at low levels throughout the developing mouse heart and human foetal (9-week) heart, it was most prominent in the conduction tissues. In the developing mouse heart, Cx40 was widely expressed at embryonic day 12.5 (E12.5) but at E17.5 expression was restricted to the conduction tissues and atria. In the 9-week human foetal heart, the Cx40 labelling pattern was similar to the E15 mouse heart, being far more abundant in conduction tissues (bundle branches to Purkinje fibres) and atria than in the ventricular muscle. Cx43 labelling became more apparent in the ventricular myocardium as development of the mouse heart progressed but was virtually undetectable in the central conduction system. In the human foetal heart Cx43 was virtually undetectable in the atria but was the predominant connexin in the ventricles. We conclude that, at least in some key aspects, the pattern of connexin expression in the developing mouse heart parallels that found in the human embryonic heart.

Animals↗
PubMed2004

Expression of genes participating in regulation of fatty acid and glucose utilization and energy metabolism in developing rat hearts.

The heart is a unique organ that can use several fuels for energy production. During development, the heart undergoes changes in fuel supply, and it must be able to respond to these changes. We have examined changes in the expression of several genes that regulate fuel transport and metabolism in rat hearts during early development. At birth, there was increased expression of fatty acid transporters and enzymes of fatty acid metabolism that allow fatty acids to become the major source of energy for cardiac muscle during the first 2 wk of life. At the same time, expression of genes that control glucose transport and oxidation was downregulated. After 2 wk, expression of genes for glucose uptake and oxidation was increased, and expression of genes for fatty acid uptake and utilization was decreased. Expression of carnitine palmitoyltransferase I (CPT I) isoforms during development was different from published data obtained from rabbit hearts. CPT Ialpha and Ibeta isoforms were both highly expressed in hearts before birth, and both increased further at birth. Only after the second week did CPT Ialpha expression decrease appreciably below the level of CPT Ibeta expression. These results represent another example of different expression patterns of CPT I isoforms among various mammalian species. In rats, changes in gene expression followed nutrient availability during development and may render cardiac fatty acid oxidation less sensitive to factors that influence malonyl-CoA content (e.g., fluctuations in glucose concentration) and thereby favor fatty acid oxidation as an energy source for cardiomyocytes in early development.

Aging↗
PubMed1999

Apoptosis in the pattern formation of the ventricular wall during mouse heart organogenesis.

Apoptosis is an important mechanism in organogenesis, but its role in heart development has been poorly characterized. We have here studied apoptosis in the developing ventricular wall of mouse embryonic heart. Developing mice hearts on days 11 to 16 of gestation were studied using in situ end-labeling of degraded DNA (TUNEL), immunocytochemistry of regulatory genes Bcl-2 and Bax, and light and electron microscopy. TUNEL end-labeled apoptotic cells were found in the ventricular wall on days 11 to 16 of gestation. The proportions of apoptotic cells of all cells in the ventricular wall differed between the trabecular and compact regions (P = 0.003) and between the days of gestation (P = 0.0001), the calculated apoptotic index was greater in the compact region at all ages except day 14. Ultrastructural analysis showed typical apoptotic shrinkage, chromatin degradation, and apoptotic bodies in several myoblastic and myocardial endothelial cells which were also positive by DNA end-labeling. Immunocytochemical reaction for the apoptosis checkpoint proteins in the ventricular wall showed clearly more Bcl-2 positive cells than Bax positive cells. The numerical densities of all cells in the compact and trabecular regions remained always higher in the compact region (P = 0.04) despite the fact that apoptosis was present in both areas at the same time. In conclusion, apoptosis takes place in the developing myocardial muscle as well as the myocardial endothelium during ventricular morphogenesis on days 11 through 16 and decreases clearly on day 16. We suggest that apoptosis and its regulatory factors are closely involved in the morphogenesis of the ventricular wall of the mammalian heart.

Animals↗
PubMed1990

Expression of dystrophin mRNA and the protein in the developing rat heart.

We examined the expression of dystrophin mRNA and the protein in the developing rat heart with polymerase chain reaction, immunoblotting and immunohistochemical analyses. Dystrophin mRNA was detectable on and after the 10th embryonic day, while the protein became detectable during the perinatal period.

Aging↗
PubMed2001

Molecular characterization of the ventricular conduction system in the developing mouse heart: topographical correlation in normal and congenitally malformed hearts.

OBJECTIVES: Within the adult heart, it is convention to distinguish the conduction system and working (atrial and ventricular) myocardium. The adult conduction system (CS) comprises the sinoatrial (SAN), and atrioventricular (AVN) nodes, the atrioventricular bundle (AVB), the bundle branches and the peripheral Purkinje fibers, each of which display distinct functional properties and distinct profile of gene expression. Characterization of the mouse cardiac conduction system during development is rudimentary at present, even though genetically-modified mice are an increasing source of information regarding cardiac function and embryonic heart development. METHODS: We have performed a detailed study of the pattern of expression of myosin heavy chain (MHC), myosin light chain (MLC), troponin I (TnI) isoforms, connexin 43 (Cx43), desmin and alpha-smooth muscle actin (alpha-SMA), in the ventricular conduction system of normal and congenitally malformed mouse hearts (iv background) from embryonic day 14.5 to 19.5. RESULTS: The AVN is characterized by co-expression of MHC and MLC isoforms and no detectable expression of Cx43, desmin or alpha-SMA. The AVB expresses betaMHC and MLC2v, but no alphaMHC, MLC2a, Cx43, desmin or alpha-SMA. The right and left bundle branches display enhanced expression of desmin and alpha-SMA but no Cx43. The normal expression profile is maintained in congenitally malformed hearts such as double-outlet right ventricle and common atrioventricular canal. Three-dimensional reconstruction of the conduction system shows normal arrangement of the bundle branches in congenitally malformed hearts, but abnormal location and/or extension of the AVN. CONCLUSIONS: Molecular characterization allows to follow the development of the CS in both, normal and malformed mouse hearts. Normal phenotypic expression of the CS is independent of heart situs but shows minor modifications in the presence of heart malformations. It is concluded that the AVN derives from the atrioventricular canal myocardium, the bundle of His from the ventricular myocardium, and the bundle branches from the ventricular trabeculations. Our results do not provide evidence to support an extra-cardiac origin of the ventricular CS.

Actins↗
PubMed2006

Differential levels of tissue hypoxia in the developing chicken heart.

Tissue hypoxia plays a critical role in normal development, including cardiogenesis. Previously, we showed that oxygen concentration, as assessed by the hypoxia indicator EF5, is lowest in the outflow tract (OFT) myocardium of the developing chicken heart and may be regulating events in OFT morphogenesis. In this study, we identified additional areas of the embryonic chicken heart that were intensely positive for EF5 within the myocardium in discrete regions of the atrial wall and the interventricular septum (IVS). The region of the IVS that is EF5-positive includes a portion of the developing central conduction system identified by HNK-1 co-immunostaining. The EF5 positive tissues were also specifically positive for nuclear-localized hypoxia inducible factor 1alpha (HIF-1alpha), the oxygen-sensitive component of the hypoxia inducible factor 1 (HIF-1) heterodimer. The pattern of the most intensely EF5-stained myocardial regions of the atria and IVS resemble the pattern of the major coronary vessels that form in later stages within or immediately adjacent to these particular regions. These vessels include the sinoatrial nodal artery that is a branch of the right coronary artery within the atrial wall and the anterior/posterior interventricular vessels of the IVS. These findings indicate that a portion of the developing central conduction system and the patterning of coronary vessels may be subject to a level of regulation that is dependent on differential oxygen concentration within cardiac tissues and subsequent HIF-1 regulation of gene expression.

Animals↗
PubMed2002

Characterization of Notch receptor expression in the developing mammalian heart and liver.

Alagille syndrome (AGS) is an autosomal dominant disorder characterized by bile duct paucity along with cardiovascular, skeletal, and ophthalmologic defects. The identification of JAG1 as the AGS disease gene revealed the crucial role of the Notch signaling pathway in the development of multiple organ systems in humans. Patients with identical mutations in JAG1 demonstrate extreme clinical variability, suggesting that other factors may influence the severity of the developmental defects in this disorder. We have defined the temporal and spatial expression patterns of the Notch receptor genes in the developing mammalian heart and liver in order to identify potential ligand/receptor interactions during embryogenesis. In the developing heart, both Notch1 and Notch2 are expressed in the outflow tracts and the epicardium, in specific cell populations previously shown to express JAG1. These cells are destined to undergo epithelial-to-mesenchymal transformation. In the newborn mouse liver, Notch2 and Notch3 are expressed in opposing cell populations, suggesting they play different roles in cell fate determination during bile duct development. JAG1 is also expressed in cells adjacent to those expressing Notch2, suggesting a possible ligand receptor relationship. The Notch receptors have distinct roles in cell fate determination in different organ systems.

Animals↗
PubMed1985

Endogenous tyrosine hydroxylase activity in the developing chick heart: a possible source of extraneuronal catecholamines.

The source of catecholamines in the developing chick heart was investigated by using catecholamine assays and tyrosine hydroxylase assays on hearts from normal and chemically-sympathectomized chick embryos. A biochemical index of sympathetic nerve development in the heart was obtained by monitoring the ability of sympathetic nerves in the atria to take up [3H]-norepinephrine in vitro. Specific neuronal uptake of [3H]-norepinephrine in atria was first detected on incubation day 11 and increased throughout the incubation period. High performance liquid chromatography with electrochemical detection was used to measure the norepinephrine concentration and content of embryonic hearts. The cardiac norepinephrine concentration fluctuated throughout the incubation period but was particularly low (0.01 +/- 0.005 ng/mg wet wt) on incubation days 10 to 13, coincident with the arrival of sympathetic nerves in the heart. The highest norepinephrine concentration was measured on incubation day 7 (2.09 +/- 0.50 ng/mg wet wt) prior to the arrival of sympathetic nerves in the heart. Sympathetic nerve axotomy produced by chronic treatment with 6-hydroxydopamine reduced [3H]-norepinephrine uptake in atria and norepinephrine concentration in whole hearts on incubation day 20 to 33 and 47% of control, respectively. Tyrosine hydroxylase activity was detected in normal hearts on incubation day 7, 3 to 4 days before the heart is innervated by sympathetic nerves. Tyrosine hydroxylase activity persisted in the heart on incubation day 20, despite treatment with 6-hydroxydopamine on incubation days 13 to 19. The tyrosine hydroxylase activity in 6-hydroxydopamine lesioned hearts was not significantly different from saline-treated controls. This data indicates that tyrosine hydroxylase activity is present in the immature chick heart prior to the arrival of sympathetic innervation and following chemical sympathectomy; hence, an extraneuronal source of tyrosine hydroxylase, the rate limiting enzyme for catecholamine biosynthesis, exists in the embryonic chick heart.

Animals↗
PubMed1997

Coordinate regulation of SR Ca(2+)-ATPase and phospholamban expression in developing murine heart.

Phospholamban, the regulator of Ca(2+)-adenosinetriphosphatase (ATPase) activity in cardiac sarcoplasmic reticulum (SR), is an important determinant of basal myocardial performance. To determine whether phospholamban expression is developmentally regulated in the mouse and whether such regulation reflects alterations in Ca2+ pump activity, hearts from different stages of development were processed for molecular biological and biochemical studies. Both phospholamban and Ca(2+)-ATPase mRNAs were approximately 40% of adult (100%) levels at birth and gradually increased to approach adult levels by day 15 of development. These changes in transcript levels were indicative of changes at the protein level for both phospholamban and Ca(2+)-ATPase. Analysis of the initial rates of Ca2+ uptake demonstrated that over the course of development the upregulation of Ca(2+)-ATPase correlated with increases in the maximal rates of Ca2+ uptake and the constant apparent stoichiometric ratio of phospholamban to Ca(2+)-ATPase correlated with maintenance of a constant affinity of this enzyme for Ca2+ (0.25 +/- 0.03 microM Ca2+). Furthermore, targeted ablation of phospholamban in the mouse resulted in a much higher affinity of Ca2+ uptake for Ca2+ (0.10 +/- 0.02 microM Ca2+) than that observed in wild-type hearts, and this increased affinity was also maintained across different stages of postnatal development. These findings suggest that phospholamban is a major regulator of the affinity of Ca(2+)-ATPase for Ca2+, and coordinate regulation of the expression levels of these two SR proteins may be necessary for maintaining Ca2+ homeostasis in the developing mammalian heart.

Aging↗
PubMed1991

Morphological innervation pattern of the developing rabbit heart.

The morphological innervation pattern of developing fetal and neonatal rabbit hearts was delineated histochemically by a cholinesterase/silver procedure and immunohistochemically with the monoclonal antibody HNK1, an antibody which recognizes some cells derived from neuroectoderm. Cholinesterase-containing nerves appeared distally on the outflow tract by gestational day 15 (G15). Isolated cells with cholinesterase-stained fine processes were present near the base of the pulmonary trunk. HNK1 antibody stained the same nerves and ganglia revealed by the cholinesterase reaction and other nerves in the rabbit heart. It was used to confirm that cells with fine neuron-like processes were present before nerve ingrowth. The G14 heart contained many HNK1 staining cells in the right atrium, outflow, and inflow tracts; cells with fine processes were few but increased at G16. By G17, a plexus of interweaving nerves and associated cells began to form at the base of the pulmonary trunk. Fine nerves encircled the base of the aorta, and others crossed the intercaval region dorsally. At G19, nerves 1) extended downward from a rich "bulbar" plexus along the front ventricular surface, 2) grew near the epicardial surface at the base of the heart along the atrial floor and ventricular roof, 3) traversed the vena cavae and intercaval region to enter the atrial roof, and 4) crossed the coronary sinus to reach the back ventricular walls. By G23, cholinesterase-staining nerves and ganglia in the atria and, epicardially, in the ventricles formed the general innervation pattern of the newborn and adult rabbit heart.

Animals↗
PubMed1993

The distribution and characterization of HNK-1 antigens in the developing avian heart.

The heart originates from splanchnic mesoderm and to a lesser extent from neural crest cells. The HNK-1 monoclonal antibody is a marker for early migrating neural crest cells, but reacts also with structures which are not derived from the neural crest. We investigated whether heart structures are HNK-1 positive before neural crest cells colonize these target tissues. To that end, we determined the HNK-1 antigen expression in the developing avian heart on immunohistochemical sections and on Western blots. The HNK-1 immunoreactivity in the developing chick heart is compared with data from literature on the localization of neural crest cells in chick/quail chimeras. Structures with neural crest contribution, including parts of the early outflow tract and the related endocardial cushions, the primordia of the semilunar valve leaflets and the aorticopulmonary septum were HNK-1 positive. Furthermore, other structures were HNK-1 positive, such as the atrioventricular cushions, the wall of the sinus venosus at stage HH 15 through 21, parts of the endocardium at E3, parts of the myocardium at E6, and the extracellular matrix in the myocardial base of the semilunar valves at E14. HNK-1 expression was particularly observed in morphologically dynamic regions such as the developing valves, the outflow tract cushion, the developing conduction system and the autonomic nervous system of the heart. We observed that atrioventricular endocardial cushions are HNK-1 positive. We conclude that: a HNK-1 immunoreactivity does not always coincide with the presence of neural crest cells or their derivatives; (2) the outflow tract cushions and atrioventricular endocardial cushions are HNK-1 positive before neural crest cells are expected (stage HH 19) to enter the endocardial cushions of the outflow tract; (3) the observed spatio-temporal HNK-1 patterns observed in the developing heart correspond with various HNK-1 antigens. Apart from a constant pattern of HNK-1 antigens during development, stage-dependent HNK-1 antigens were also found.

Animals↗
PubMed1999

Myosin light chain 2a and 2v identifies the embryonic outflow tract myocardium in the developing rodent heart.

The embryonic heart consists of five segments comprising the fast-conducting atrial and ventricular segments flanked by slow-conducting segments, i.e. inflow tract, atrioventricular canal and outflow tract. Although the incorporation of the flanking segments into the definitive atrial and ventricular chambers with development is generally accepted now, the contribution of the outflow tract myocardium to the definitive ventricles remained controversial mainly due to the lack of appropriate markers. For that reason we performed a detailed study of the pattern of expression of myosin light chain (MLC) 2a and 2v by in situ hybridization and immunohistochemistry during rat and mouse heart development. Expression of MLC2a mRNA displays a postero-anterior gradient in the tubular heart. In the embryonic heart it is down-regulated in the ventricular compartment and remains high in the outflow tract, atrioventricular canal, atria and inflow tract myocardium. MLC2v is strongly expressed in the ventricular myocardium and distinctly lower in the outflow tract and atrioventricular canal. The co-expression of MLC2a and MLC2v in the outflow tract and atrioventricular canal, together with the single expression in the atrial (MLC2a) and ventricular (MLC2v) myocardium, permits the delineation of their boundaries. With development, myocardial cells are observed in the lower endocardial ridges that share MLC2a and MLC2v expression with the myocardial cells of the outflow tract. In neonates, MLC2a continues to be expressed around both right and left semilunar valves, the outlet septum and the non-trabeculated right ventricular outlet. These findings demonstrate the contribution of the outflow tract to the definitive ventricles and demonstrate that the outlet septum is derived from outflow tract myocardium.

Animals↗
PubMed1992

Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions.

BACKGROUND: It is not known whether the treatment of patients with asymptomatic left ventricular dysfunction reduces mortality and morbidity. We studied the effect of an angiotensin-converting--enzyme inhibitor, enalapril, on total mortality and mortality from cardiovascular causes, the development of heart failure, and hospitalization for heart failure among patients with ejection fractions of 0.35 or less who were not receiving drug treatment for heart failure. METHODS: Patients were randomly assigned to receive either placebo (n = 2117) or enalapril (n = 2111) at doses of 2.5 to 20 mg per day in a double-blind trial. Follow-up averaged 37.4 months. RESULTS: There were 334 deaths in the placebo group, as compared with 313 in the enalapril group (reduction in risk, 8 percent by the log-rank test; 95 percent confidence interval, -8 percent [an increase of 8 percent] to 21 percent; P = 0.30). The reduction in mortality from cardiovascular causes was larger but was not statistically significant (298 deaths in the placebo group vs. 265 in the enalapril group; risk reduction, 12 percent; 95 percent confidence interval, -3 to 26 percent; P = 0.12). When we combined patients in whom heart failure developed and those who died, the total number of deaths and cases of heart failure was lower in the enalapril group than in the placebo group (630 vs. 818; risk reduction, 29 percent; 95 percent confidence interval, 21 to 36 percent; P less than 0.001). In addition, fewer patients given enalapril died or were hospitalized for heart failure (434 in the enalapril group; vs. 518 in the placebo group; risk reduction, 20 percent; 95 percent confidence interval, 9 to 30 percent; P less than 0.001). CONCLUSIONS: The angiotensin-converting--enzyme inhibitor enalapril significantly reduced the incidence of heart failure and the rate of related hospitalizations, as compared with the rates in the group given placebo, among patients with asymptomatic left ventricular dysfunction. There was also a trend toward fewer deaths due to cardiovascular causes among the patients who received enalapril.

Blood Pressure↗
PubMed1983

Detection of antineoplastic agent induced cardiotoxicity by 31P NMR of perfused rat hearts.

Development of dose dependent chronic irreversible cardiotoxicity is a key problem encountered in chemotherapy with adriamycin. Here it has been demonstrated that infusion of this agent produced distinct and largely irreversible changes in levels of phosphate metabolites and substantial acidosis that are detected by 31P NMR of the Langendorf perfused heart. Administration of the antioxidant, butylated hydroxytoluene minimizes these spectral changes but does not substantially diminish the antineoplastic activity of adriamycin. Bisantrene (CL 216,942), a noncardiotoxic anthracene with antineoplastic activity, produces only minor perturbations of the 31P spectrum of the perfused rat heart. These studies demonstrate the potential utility of employing 31P NMR to monitor acute or chronic cardiotoxicity in the perfused rat heart and for developing noninvasive in vivo NMR techniques for monitoring cardiotoxicity in experimental animals and humans.

Animals↗
PubMed1990

Functional and morphological characteristics of compensated and decompensated cardiac hypertrophy in dogs with chronic infrarenal aorto-caval fistulas.

The relation between cardiac hypertrophy, shunt size, myocardial contractility, capillary density, adrenergic responsiveness, and neurohumoral stimulation was evaluated in dogs with compensated and decompensated cardiac hypertrophy caused by an infrarenal aorto-caval shunt. Shunt size varied from 5 to 35 mm2 due to an inability to create a uniform size. Dogs that developed heart failure within 4 months had 25 +/- 2 mm2 shunts, whereas those that developed it after 4 months had 19 +/- 3 mm2 shunts; those that did not develop heart failure had 10 +/- 1 mm2 shunts. Hypertrophy developed at the same rate in all the dogs that developed heart failure, which occurred at a critical heart weight (hypertrophy) for a given load (shunt size). In the dogs with heart failure there was a decrease in myocardial contractility (tension = 5.7 +/- 0.6 vs. 7.3 +/- 0.3 g/mm2, p less than 0.05), a decrease in adrenergic responsiveness (maximal heart rate with isoproterenol = 203 +/- 7 vs. 249 +/- 5 beats/min, p less than 0.01), an increase in circulating neurohormones, and a decrease in urinary sodium excretion (0.4 +/- 0.1 vs. 5.0 +/- 1.3 meq/3 hr, p less than 0.01). None of these abnormalities occurred in dogs with compensated hypertrophy. There were no differences in cardiac capillary density between the control dogs and the dogs with compensated cardiac hypertrophy or heart failure. Thus, it would appear that if heart failure is to develop after an initial toleration of a sudden volume overload, it will develop at a given combination of cardiac hypertrophy and volume overload, with cardiac hypertrophy developing at the same rate in all cases. In this model, once heart failure develops, myocardial contractility and cardiac adrenergic responsiveness are decreased and there is pronounced neurohumoral activation. All these changes are absent in hearts with compensated hypertrophy.

Adaptation, Physiological↗
PubMed2005

Atrioventricular cushion transformation is mediated by ALK2 in the developing mouse heart.

Developmental abnormalities in endocardial cushions frequently contribute to congenital heart malformations including septal and valvular defects. While compelling evidence has been presented to demonstrate that members of the TGF-beta superfamily are capable of inducing endothelial-to-mesenchymal transdifferentiation in the atrioventricular canal, and thus play a key role in formation of endocardial cushions, the detailed signaling mechanisms of this important developmental process, especially in vivo, are still poorly known. Several type I receptors (ALKs) for members of the TGF-beta superfamily are expressed in the myocardium and endocardium of the developing heart, including the atrioventricular canal. However, analysis of their functional role during mammalian development has been significantly complicated by the fact that deletion of the type I receptors in mouse embryos often leads to early embryonal lethality. Here, we used the Cre/loxP system for endothelial-specific deletion of the type I receptor Alk2 in mouse embryos. The endothelial-specific Alk2 mutant mice display defects in atrioventricular septa and valves, which result from a failure of endocardial cells to appropriately transdifferentiate into the mesenchyme in the AV canal. Endocardial cells deficient in Alk2 demonstrate decreased expression of Msx1 and Snail, and reduced phosphorylation of BMP and TGF-beta Smads. Moreover, we show that endocardial cells lacking Alk2 fail to delaminate from AV canal explants. Collectively, these results indicate that the BMP type I receptor ALK2 in endothelial cells plays a critical non-redundant role in early phases of endocardial cushion formation during cardiac morphogenesis.

Activin Receptors, Type I↗