Gene expression specific for heart atria and ventricles]

The data on the chamber-specific expression of cardiac genes in the animal and human heart are reviewed. The positional specification of atrial and ventricular gene expression observed in adults is initiated early during embryogenesis. The existence of a cascade of genes is assumed, beginning with genes whose products form an anterior-posterior gradient along the heart-forming regions or along the linear heart tube derived from these regions, and ending with genes that encode the contractile proteins and display chamber-specific expression.     

Developmental patterns of expression and coexpression of myosin heavy chains in atria and ventricles of the avian heart

Monoclonal antibodies (mAbs), electrophoresis, immunoblotting, and immunohistochemistry were used to determine the molecular properties of cardiac myosin heavy chain (MHC) isoforms and the regions of the developing chicken heart in which they were expressed. Adult atria expressed three electrophoretically distinct MHCs that reacted specifically with mAbs F18, F59, or S58. During embryonic Days 2-4, when the atrial and ventricular chambers are forming, MHCs that reacted with mAbs F18, F59, or S58 were expressed in both the atria and ventricles. The atria continued to express MHCs that reacted with mAbs F18, F59, or S58 at all stages of development and in the adult. In the ventricles, expression of the MHCs reacting with these mAbs was found to be developmentally regulated. By embryonic Day 16, MHC(s) reacting with mAb F18 had disappeared from the developing ventricles, whereas MHCs reacting with S58 and F59 continued to be expressed throughout the ventricles. As development continued, MHC(s) reacting with S58 in the ventricle became restricted to expression in only the ventricular conducting system. MHC(s) reacting with F59 were expressed in both the ventricular myocytes and the ventricular conducting system throughout development and in the adult. Thus, in contrast to the embryonic chicken heart where at least three MHC isoforms were expressed in both the atria and ventricles, we found in the adult chicken heart that-at a minimum-three MHC isoforms were expressed in the atria, two MHC isoforms were expressed in the ventricular conducting system, and one MHC isoform in the ventricular myocardium. MHC isoform expression in the developing avian heart appears to be more complex than previously recognized.     

Fluorescence and electron-microscopic analysis of differentiation of the myocytes of the ventricles and atria of the avaian heart in ontogenesis]

The histogenesis of the ventricle and atria myocardium was studied in 240 chick embryos of from 30--34 hours up to 20 days of incubation and in 66 chickens at the age of 1--90 days. Fixators were the Bouin's Carnoy's and Newkomer's fluids and the 100% solution of neutral formalin. The paraffin sections were stained by histological and histochemical methods. RNA, DNA, glycogen and lipids were detected. The ultrafine sections of the material fixed in 1% buffer solution of osmium tetroxide (pH 7,2) and embedded in araldite were prepared for electron microscopy. The contrasting was made in solutions of acetic uranium and lead citrate. Electron microscope--UEMB-100K, accelarating voltage--75 kV. The prefunctional period of cardiogenesis is characterized by most intensive processes of specific differentiation of cardiac myocytes and by accumulation of energetic material. With the growing functional activity of the tubular heart the amount and size of lipid drops in the cytoplasm of differentiating cardiomyocytes diminished suggesting the use of lipids as the main source of energy. In the period of formation of the heart the trabecular myocardium of ventricles and the atria myocardium, seeming to perform the main functional load, are characterized by a better developed contracting apparatus and a considerable content of glycogen granules. A sharp decrease of the glycogen content at the end of the embryonic period is likely to be due to growing hypoxia, the appearance of lung respiration and transition to the other type of energy metabolism.     

Isolation and characterization of glycosaminoglycans from atria of the human heart

• 1.1. Five glycosaminoglycans were isolated from tryptic digest of atria of the human heart and were assayed by determining the carbohydrate content of materials.
• 2.2. Separation of these 5 polymers was achieved by Dowex 1 × 2 column chromatography.
• 3.3. They were identified as hyaluronic acid, heparan sulfate, chondroitin-4-sulfate, dermatan sulfate and chondroitin-6-sulfate, respectively.

     

Distribution of atrial natriuretic factor in fetal rat atria and ventricles

Summary An immunohistochemical study of rat fetal hearts at 20 days of gestation revealed the presence of immunoreactive atrial natriuretic factor (ANF) in cardiocytes of the left and right atria as well as in certain cells is the left and right ventricles. In the atria, cells of the adluminal pectinate muscles appear more densely labeled than the more peripheral mural cells. In the ventricles, immunoreactive cells were found only in adluminal cardiocytes of the presumptive trabeculae and papillary muscles. The results indicate that ANF is synthesized in the perinatal heart, and that the presence of this hormone in the ventricular cardiocytes may be of only temporary nature during certain stages of pre- and postnatal development.Supported by Miami Valley Chapter of American Heart Association MVH-86-019 and MVH-86-010     

Immuno-electron microscopy of atrial natriuretic factor secretory pathways in atria and ventricles of control and cardiomyopathic hamsters with heart failure

Summary The secretory pathways of atrial natriuretic factor have been investigated in atrial and ventricular cardiocytes of control and cardiomyopathic Syrian hamsters in severe congestive heart failure with four antibodies: a monoclonal antibody (2H2) against rat synthetic atrial natriuretic factor (101–126), which is directed against region 101–103 of rat atrial natriuretic factor (99–126), and polyclonal, affinity-purified antibodies produced in rabbits against synthetic C-terminal atrial natriuretic factor (101–126), synthetic N-terminal atrial natriuretic factor (11–37) or the putative cleavage site of atrial natriuretic factor (98–99): atrial natriuretic factor (94–103). Application of the immunogold technique on thin frozen sections (immunocryoultramicrotomy) revealed an identical picture with the four antibodies. In atria of both control and cardiomyopathic hamsters where atrial natriuretic factor secretion is regulated, the atrial natriuretic factor propeptide travels, uncleaved, from the Golgi complex to immature and mature secretory granules. In ventricles of control hamsters, where secretion is constitutive, the atrial natriuretic factor propeptide travels from the Golgi complex to secretory vesicles. In the ventricles of hamsters with severe congestive heart failure, the Golgi complex is larger, secretory vesicles more abundant and a few secretory granules are present in 20% of cardiocytes. Here again, the peptide travels uncleaved in all these pathways. These results reveal the pathways of secretion of atrial natriuretic factor in atrial and ventricular cardiocytes and indicate that the propeptide is not cleaved intracellularly.Supported by a grant from the Medical Research Council of Canada to the Multidisciplinary Research Group on Hypertension, by the Canadian Heart Foundation and the Pfizer Company (England)     

A comparison of myosin light chain subunits in the atria and ventricles of mammals

An SDS-electrophoretic comparison of atrial and ventricular myosin light chain isotypes was performed in mouse, rat, rabbit, dog, pig, rhesus monkey, baboon, human and cow heart. Light chains 1 and 2 in atria and ventricles differed in all species with the possible exception of the rhesus monkey. Relative migration of atrial and ventricular LC-2 isotypes was similar in all species but LC-1 isotypes varied in relative migration rates suggesting increased primary sequence heterogeneity. Order of migration was VLC-1 less than ALC-1 less than ALC-2 less than VLC-2 in mouse, rat, rabbit, dog, baboon and cow and ALC-1 less than VLC-1 less than ALC-2 less than VLC-2 in pig and human heart. No obvious relationship existed between electrophoretic pattern and phylogenetic evolution.     

Gene expression of the phenylethanolamine N-methyltransferase is differently modulated in cardiac atria and ventricles

Phenylethanolamine N-methyltransferase (PNMT) is a final enzyme in catecholamine synthesizing cascade that converts noradrenaline to adrenaline. Although most profuse in adrenal medulla, PNMT is expressed also in the heart, particularly in cardiac atria and ventricles. In atria, the PNMT mRNA is much more abundant compared to ventricles. In present study we aimed to find out whether there is a difference in modulation of the PNMT gene expression in cardiac atria and ventricles. We used three methodological approaches: cold as a model of mild stress, hypoxia as a model of cardiac ischemic injury, and transgenic rats (TGR) with incorporated mouse renin gene (mREN-2)27, to determine involvement of renin-angiotensin pathway in the PNMT gene expression. We have found that PNMT gene expression was modulated differently in cardiac atria and ventricles. In atria, PNMT mRNA levels were increased by hypoxia, while cold stress decreased PNMT mRNA levels. In ventricles, no significant changes were observed by cold or hypoxia. On the other hand, angiotensin II elevated PNMT gene expression in ventricles, but not in atria. These results suggest that PNMT gene expression is modulated differently in cardiac atria and ventricles and might result in different physiological consequences.     

Thyroid hormones differentially affect sarcoplasmic reticulum function in rat atria and ventricles

The present study was undertaken to compare the effects of hypothyroidism and hyperthyroidism on sarcoplasmic reticulum (SR) Ca²⁺-pump activity, together with assessment of the functional role of SR in providing activator Ca²⁺ under these altered thyroid states. In response to a shift from hypothyroid to hyperthyroid state, a 10 fold and 2 fold increase in SR Ca²⁺-pump activity in atria and ventricles, respectively, were observed. This was associated with the 8-9 fold increases in atrial contractility (+dT/dt) and relaxation (-dT/dt), but only with a 3-4 fold increase in their ventricular counterparts. Also, the recirculation fraction of activator Ca²⁺ (RFA) increased to a far greater extent in atria (4 fold) than in papillary muscles, and the relative increment in inhibition of developed tension by ryanodine became 3 times larger in atria than in papillary muscles. A positive force-frequency relationship (FFR) was observed in hypothyroid atria, whereas the hyperthyroid atria, hypothyroid and hyperthyroid papillary muscles showed a negative FFR. These results suggest the greater role of transsarcolemmal (SL) Ca²⁺ and smaller role of SR Ca²⁺ in activating contraction in hypothyroid atria compared to other preparations. Thyroid hormones decrease the contribution of SL and increase that of SR in providing activator Ca²⁺ to the greater extent in atria than in ventricles. This effect of thyroid hormones is based on larger stimulation of SR Ca²⁺-pump in atria compared to ventricles.     

Development of different electrophysiological mechanisms for muscarinic inhibition of atria and ventricles

The negative inotropic effect of acetylcholine (ACh) in atrial muscle can be accounted for by a decrease of a voltage- and time-dependent slow inward current (Isi) carried by Ca2+/Na+ and an increase of outward time-dependent current carried by K+ (IK1) through inwardly rectifying channels. The negative inotropic effect of ACh in ventricular muscle is associated with a reduction of Isi; there is no important effect of ACh on IK1 in ventricular muscle. Because atrial and ventricular muscles display IK1 that is sensitive to Ba2+ and have similar numbers of muscarinic receptor sites, it is concluded that ventricular muscle lacks a metabolic link between the muscarinic receptor and inwardly rectifying K+ channels. Although there is much evidence for cyclic nucleotides as the mediator between muscarinic receptors and Isi channels, cyclic nucleotides do not seem to connect these receptors with inwardly rectifying K+ channels. According to this hypothesis, identification of a metabolic link between muscarinic receptors and IK1 channels should be demonstrable in atrial but not ventricular muscle.     

Comparative effects of dihydropyridine inhibitors of calcium penetration on spontaneous contraction of the isolated heart atria in the guinea pig

All DHPs (nifedipine, nicardipine, nitrendipine) produced a concentration-dependent depression of the isometric contraction and of the atrial rate of the isolated, spontaneously beating atria of the guinea-pig. The depressive actions of nifedipine and nitrendipine were completely antagonized by the addition of calcium, aminophylline and isoprenaline. Aminophylline partially, calcium almost completely and isoprenaline completely antagonized the depressive action of nicardipine on the isometric contraction. Only isoprenaline antagonized the effect of DHPs on the atrial rate of the isolated, spontaneously beating atria of the guinea-pig. It is possible that all these substances restore the contractibility of the atria by compensating the calcium balance, previously changed by DHPs, or by producing an increase in the intracellular cyclic AMP content (aminophylline and isoprenaline).     

A model of heart ventricles for electrocardiographic evaluation of the state of the myocardium

A mathematical model of heart excitation processes has been developed for describing an electrocardiogram. A verified archive of model electrocardiograms has been created with the use of the model. The model has been used to study how electrocardiograms are affected by individual variability in ventricle shape and heart position in the norm, in myocardial infarction of different localizations, and in ventricular hypertrophy. Correspondence of the specific features of real and model electrocardiograms is discussed.     

Modelling of the heart and pericardium at end-diastole

Herein we present a refined version of Vito's two-sphere static model of the heart with pericardium and discuss its possible applications. The improvements we make on Vito's model are: (i) Vito assumed that the elastic materials which constitute the model 'heart' and 'pericardium' are isotropic; we relax this assumption to that of transverse-isotropy. (ii) Our analysis, which does not assume the existence of stored-energy functions, links the model directly to empirical stress-strain relations of suitable biaxial uniform-extension tests; two such stress-strain relations (one for the pericardium, one for the myocardium, both of which may be described by the same equation except for difference in the values of response parameters) now define the model completely, so we avoid altogether the difficult task of determining full-fledged constitutive equations for the pericardium and myocardium. As for applications, we contend that the concentric spheres in static equilibrium can be taken as a model of the left ventricle and pericardium at end-diastole. We show that the model when equipped with suitable stress-strain relations does give good fit to the pressure-volume data which Spotnitz et al. (1966, Circulation Res., 18, 49-66) obtained from excised canine left ventricles and to the pericardium data which Pegram et al. (1975, Circulation Res., 9, 707-714) obtained from closed chest, anaesthetized dogs. Three different empirical formulae were tried in the data-fitting as the equation that describes the requisite stress-strain relations. The 'exponential law' gave the best results.     

Differential regulation of SR calcium transporters by thyroid hormone in rat atria and ventricles

Thyroid hormone exerts positive inotropic effects on the heart mediated in part by its regulation of calcium transporter proteins, including sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA2), phospholamban (PLB), and Na(+)/Ca(2+) exchanger (NCX). To further understand the potential cardiac chamber-specific effects of thyroid hormone action, we compared the triiodo-L-thyronine (T(3)) responsiveness of calcium transporter proteins in atrial versus ventricular tissues. Rats were rendered hypothyroid by ingestion of propylthiouracil, and a subgroup of animals was treated with T(3) for 7 days (7 microg/day by constant infusion). Atrial and left ventricular (LV) tissue homogenates were analyzed for expression of SERCA2, PLB, and NCX proteins by Western blot analysis. SERCA2 protein significantly decreased by 50% in hypothyroid LV and was normalized by T(3) treatment. In contrast, SERCA2 protein in atria was unaltered in the hypothyroid state. PLB protein expression significantly increased by 1.6- and 5-fold in the hypothyroid LV and atria, respectively, and returned to euthyroid levels with T(3) treatment. Expression of NCX protein showed a greater response to T(3) treatment in atria tissue than in ventricular tissue. Sarcoplasmic reticulum calcium cycling is determined in part by the ratio of SERCA2 to PLB. This ratio was sixfold higher in the atria compared with LV, suggesting that PLB may play a minor role in the regulation of SERCA2 function in normal atria. We conclude that calcium transporter proteins are responsive to thyroid hormone in a chamber-specific manner, with atria showing a greater change in protein content in response to T(3). The differential effect on atria may account for the occurrence of atrial rather than ventricular arrhythmias in response to even mild degrees of thyrotoxicosis.     

Human cardiac myosin heavy chain isoforms in fetal and failing adult atria and ventricles

The goal of this study was to test the hypothesis that the relative amounts of the cardiac myosin heavy chain (MHC) isoforms MHC-alpha and MHC-beta change during development and transition to heart failure in the human myocardium. The relative amounts of MHC-alpha and MHC-beta in ventricular and atrial samples from fetal (gestational days 47--110) and nonfailing and failing adult hearts were determined. The majority of the fetal right and left ventricular samples contained small relative amounts of MHC-alpha (mean < 5% of total MHC). There was a small significant decrease in the level of MHC-alpha in the ventricles between 7 and 12 wk of gestation. Fetal atria expressed predominantly MHC-alpha (mean > 95%), with MHC-beta being detected in most samples. The majority of adult nonfailing right and left ventricular samples had detectable levels of MHC-alpha ranging from 1 to 10%. Failing right and left ventricles expressed a significantly lower level of MHC-alpha. MHC-alpha comprised approximately 90% of the total MHC in adult nonfailing left atria, whereas the relative amount of MHC-alpha in the left atria of individuals with dilated or ischemic cardiomyopathy was approximately 50%. The differences in MHC isoform composition between fetal and nonfailing adult atria and between fetal and nonfailing adult ventricles were not statistically significant. We concluded that the MHC isoform compositions of fetal human atria are the same as those of nonfailing adult atria and that the ventricular MHC isoform composition is different between adult nonfailing and failing hearts. Furthermore, the marked alteration in atrial MHC isoform composition, associated with cardiomyopathy, does not represent a regression to a pattern that is uniquely characteristic of the fetal stage.     

A 2D FE model of the heart demonstrates the role of the pericardium in ventricular deformation

During pulmonary artery constriction (PAC), an experimental model of acute right ventricular (RV) pressure overload, the interventricular septum flattens and inverts. Finite element (FE) analysis has shown that the septum is subject to axial compression and bending when so deformed. This study examines the effects of acute PAC on the left ventricular (LV) free wall and the role the pericardium may play in these effects. In eight open-chest anesthetized dogs, LV, RV, aortic, and pericardial pressures were recorded under control conditions and with PAC. Model dimensions were derived from two-dimensional echocardiography minor-axis images of the heart. At control (pericardium closed), FE analysis showed that the septum was concave to the LV; stresses in the LV, RV, and septum were low; and the pericardium was subject to circumferential tension. With PAC, RV end-diastolic pressure exceeded LV pressure and the septum inverted. Compressive stresses developed circumferentially in the septum out to the RV insertion points, forming an arch-like pattern. Sharp bending occurred near the insertion points, accompanied by flattening of the LV free wall. With the pericardium open, the deformations and stresses were different. The RV became much larger, especially with PAC. With PAC, the arch-like circumferential stresses still developed in the septum, but their magnitudes were reduced, compared with the pericardium-closed case. There was no free wall inversion and flattening was less. From these FE results, the pericardium has a significant influence on the structural behavior of the septum and the LV and RV free walls. Furthermore, the deformation of the heart is dependent on whether the pericardium is open or closed.     

A model of heart ventricles for describing electrocardiograms in the estimation of the state of the myocardium

A mathematical model of heart excitation processes for describing the electrocardiograms was developed. By using the model, it is possible to create a verified archive of model electrocardiograms and study the effect of individual variability of ventricle shape and the position of the heart in norm, in infarctions of different localization, and in ventricle hypertrophy. The consistency of real electrocardiograms with those obtained by computer-assisted modeling is discussed.