Making more heart muscle

Postnatally, heart muscle cells almost completely lose their ability to divide, which makes their loss after trauma irreversible. Potential repair by cell grafting or mobilizing endogenous cells is of particular interest for possible treatments for heart disease, where the poor capacity for cardiomyocyte proliferation probably contributes to the irreversibility of heart failure. Knowledge of the molecular mechanisms that underly formation of heart muscle cells might provide opportunities to repair the diseased heart by induction of (trans) differentiation of endogenous or exogenous cells into heart muscle cells. We briefly review the molecular mechanisms involved in early development of the linear heart tube by differentiation of mesodermal cells into heart muscle cells. Because the initial heart tube does not comprise all the cardiac compartments present in the adult heart, heart muscle cells are added to the distal borders of the tube and within the tube. At both distal borders, mesodermal cell are recruited into the cardiac lineage and, within the heart tube, muscular septa are formed. In this review, the relative late additions of heart muscle cells to the linear heart tube are described and the potential underlying molecular mechanisms are discussed.     

Neural transmitters and a peptide modulate Drosophila heart rate

Neural messengers affect Drosophila heart rate. Serotonin increases larval, pupal, and adult heart rate. Octopamine and dopamine are inactive in larva, decrease pupal rate, and increase adult heart rate. Acetylcholine and nicotine decrease larval and pupal heart rate, while acetylcholine decreases and nicotine increases adult heart rate. Muscarine decreases pupal heart rate, but is inactive in larva and adult. GABA is inactive in larva and adult, but decreases pupal heart rate. Glutamate is inactive in larva and pupa, but decreases adult heart rate. Proctolin decreases heart rate in all three stages. Caffeine acts only to decrease adult heart rate.     

Ketone metabolism in the failing heart

The high energy demands of the heart are met primarily by the mitochondrial oxidation of fatty acids and glucose. However, in heart failure there is a decrease in cardiac mitochondrial oxidative metabolism and glucose oxidation that can lead to an energy starved heart. Ketone bodies are readily oxidized by the heart, and can provide an additional source of energy for the failing heart. Ketone oxidation is increased in the failing heart, which may be an adaptive response to lessen the severity of heart failure. While ketone have been widely touted as a “thrifty fuel”, increasing ketone oxidation in the heart does not increase cardiac efficiency (cardiac work/oxygen consumed), but rather does provide an additional fuel source for the failing heart. Increasing ketone supply to the heart and increasing mitochondrial ketone oxidation increases mitochondrial tricarboxylic acid cycle activity. In support of this, increasing circulating ketone by iv infusion of ketone bodies acutely improves heart function in heart failure patients. Chronically, treatment with sodium glucose co-transporter 2 inhibitors, which decreases the severity of heart failure, also increases ketone body supply to the heart. While ketogenic diets increase circulating ketone levels, minimal benefit on cardiac function in heart failure has been observed, possibly due to the fact that these dietary regimens also markedly increase circulating fatty acids. Recent studies, however, have suggested that administration of ketone ester cocktails may improve cardiac function in heart failure. Combined, emerging data suggests that increasing cardiac ketone oxidation may be a therapeutic strategy to treat heart failure.     

Effect of heart weight on distribution of lung surface pressures in vertical dogs

In head-up dogs the vertical gradient of transpulmonary pressure (VGTP) disappears after pneumothorax develops. Our laboratory recently confirmed that the heart moves downward and posteriorly with pneumothorax. To study the extent to which the heart is supported by the lungs, we used a linear elasticity model and finite-element analysis. The lung and heart were assumed to be symmetric along a vertical axis. Reported values of the elastic properties of lung and heart were assigned. The model was generated first without the heart, using the lung alone. The heart was then added to the model. Finally, heart weight was doubled. Adding the heart caused the VGTP to increase; doubling the heart weight further increased the VGTP. These increases were more pronounced at higher lung volumes. Lung inflation was accompanied by an upward displacement of the heart. Inclusion of the heart caused increased inhomogeneities in regional volume distribution. The effect of heart weight may in part explain why the VGTP in the head-up dog is greater than that predicted by lung density.     

应用三元递减法筛选特异性心脏生长相关基因

心脏是由胚胎干细胞特异性分化而来的 ,但其分化的分子生物学机制尚不十分了解 .为建立一种新的筛选特异性心脏相关基因的方法 ,克隆特异性心脏生长相关基因 .从胚胎心、成年心和去胎心的胚胎中提取 m RNA,建立胎心 /成年心和胎心 /胎身两个递减性 c DNA文库 ,通过 DNA芯片和微阵列杂交筛选和克隆 ,建立了三元递减克隆的新方法 .获得了一个全长为 1 0 0 6 bp可编码1 94个氨基酸的新的与心脏生长相关的基因 ,它是 LIM家族的新成员 ,可特异性在心肌细胞表达 ,并可促进心肌细胞的生长 .结果表明 ,三元递减筛选法可以应用于寻找新的组织特异性表达的基因 .并且获得了一个新的与心脏生长相关的新基因 ,它可能在心肌生长和心肌肥厚的发生中发挥重要作用     

Single neurone responses to tactile stimulation of the heart in the snail,Helix pomatia L.

Summary The electrical activity of the heart nerve and of single neurons in the suboesophageal ganglia were recorded during tactile stimulation of the heart. 15 neurons were identified which responded to heart stimulation by inhibiting or accelerating activity. Cells influenced by heart afferents are scattered in the visceral and in the right and left parietal ganglia.In most of the cases both decrease and increase of cell activity are caused by synaptic potentials, in some cases, however, the neuron is assumed to have a sensory character.The activity of three neurons influenced by heart stimulation was conducted into the heart nerve. These cells are central neurons of a heart-CNS-heart reflex.Some of the neurons located in the right parietal and visceral ganglia have no connection with the mechanoreceptors of the heart. Since their spikes propagate into the heart nerve, they probably take part in the extracardial regulation of heart activity.One of the neurons located in the visceral ganglion (cell V12) sends its axon into the heart nerve. The response of this neuron to heart stimulation was an increase in activity and an inhibition of the heart rate. This is an inhibitory neuron of the extracardial heart regulatory system.     

Joint dynamic imaging of morphogenesis and function in the developing heart

In the developing heart, time-lapse imaging is particularly challenging. Changes in heart morphology due to tissue growth or long-term reorganization are difficult to follow because they are much subtler than the rapid shape changes induced by the heartbeat. Therefore, imaging heart development usually requires slowing or stopping the heart. This, however, leads to information loss about the unperturbed heart shape and the dynamics of heart function. To overcome this limitation, we have developed a non-invasive heart imaging technique to jointly document heart function (at fixed stages of development) as well as its morphogenesis (at any fixed phase in the heartbeat) that does not require stopping or slowing the heart. We review the challenges for imaging heart development and our methodology, which is based on computationally combining and analyzing multiple high-speed image sequences acquired throughout the course of development. We present results obtained in the developing zebrafish heart. Image analysis of the acquired data yielded blood flow velocity maps and made it possible to follow the relative movement of individual cells over several hours.     

A role for BMP signalling in heart looping morphogenesis in Xenopus

The heart develops from a linear tubular precursor, which loops to the right and undergoes terminal differentiation to form the multichambered heart. Heart looping is the earliest manifestation of left-right asymmetry and determines the eventual heart situs. The signalling processes that impart laterality to the unlooped heart tube and thus allow the developing organ to interpret the left-right axis of the embryo are poorly understood. Recent experiments in zebrafish led to the suggestion that bone morphogenetic protein 4 (BMP4) may impart laterality to the developing heart tube. Here we show that in Xenopus, as in zebrafish, BMP4 is expressed predominantly on the left of the linear heart tube. Furthermore we demonstrate that ectopic expression of Xenopus nodal-related protein 1 (Xnr1) RNA affects BMP4 expression in the heart, linking asymmetric BMP4 expression to the left-right axis. We show that transgenic embryos overexpressing BMP4 bilaterally in the heart tube tend towards a randomisation of heart situs in an otherwise intact left-right axis. Additionally, inhibition of BMP signalling by expressing noggin or a truncated, dominant negative BMP receptor prevents heart looping but allows the initial events of chamber specification and anteroposterior morphogenesis to occur. Thus in Xenopus asymmetric BMP4 expression links heart development to the left-right axis, by being both controlled by Xnr1 expression and necessary for heart looping morphogenesis.     

Restoration of the heart activity in deep hypothermia with the aid of norepinephrine and no warming of the heart

A possibility of restoration and stimulation of the rat isolated heart contractions in deep hypothermia by means of norepinephrine (6 microM) was studied. Following a complete arrest of the heart at a retrograde perfusion with the Krebs-Henseleit buffer ([K+] 5.9 mM), norepinephrine was found to restore the heart beats and to lower the heart arrest temperature from 8.2 +/- 0.5 degrees to 6.6 +/- 0.3 degrees. At the perfusion with the Krebs-Henseleit buffer, the heart rate dropped to below 10 min(-1) at 13.0 +/- 0.9 degrees. Reduction of [K+] to 2.95 mM intensified the heart rate. At a progressing cooling, the heart rate lower than 10 min(-1) occurred at 10.9 +/- 0.6 degrees. When adding norepinephrine (6 microM) to the perfusion fluid with [K+] 2.95 mM, the heart rate increased once again (on the average to 23.1 +/- 5.3 min(-1)) despite the fact that the heart temperature continued to be lowered. The heart rate lower than 10 min(-1) was reached at the progressing cooling to, on the average, 9.6 +/- 0.7 degrees. The findings show norepinephrine to exert a stimulating effect on the heart activity even at such low heart temperatures as 7-10 degrees with no preliminary warming of the heart.     

Conotruncal myocardium arises from a secondary heart field.

The primary heart tube is an endocardial tube, ensheathed by myocardial cells, that develops from bilateral primary heart fields located in the lateral plate mesoderm. Earlier mapping studies of the heart fields performed in whole embryo cultures indicate that all of the myocardium of the developed heart originates from the primary heart fields. In contrast, marking experiments in ovo suggest that the atrioventricular canal, atria and conotruncus are added secondarily to the straight heart tube during looping. The results we present resolve this issue by showing that the heart tube elongates during looping, concomitant with accretion of new myocardium. The atria are added progressively from the caudal primary heart fields bilaterally, while the myocardium of the conotruncus is elongated from a midline secondary heart field of splanchnic mesoderm beneath the floor of the foregut. Cells in the secondary heart field express Nkx2.5 and Gata-4, as do the cells of the primary heart fields. Induction of myocardium appears to be unnecessary at the inflow pole, while it occurs at the outflow pole of the heart. Accretion of myocardium at the junction of the inflow myocardium with dorsal mesocardium is completed at stage 12 and later (stage 18) from the secondary heart field just caudal to the outflow tract. Induction of myocardium appears to move in a caudal direction as the outflow tract translocates caudally relative to the pharyngeal arches. As the cells in the secondary heart field begin to move into the outflow or inflow myocardium, they express HNK-1 initially and then MF-20, a marker for myosin heavy chain. FGF-8 and BMP-2 are present in the ventral pharynx and secondary heart field/outflow myocardium, respectively, and appear to effect induction of the cells in a manner that mimics induction of the primary myocardium from the primary heart fields. Neither FGF-8 nor BMP-2 is present as inflow myocardium is added from the primary heart fields. The addition of a secondary myocardium to the primary heart tube provides a new framework for understanding several null mutations in mice that cause defective heart development.     

Comparative study of myocardial high energy phosphate substrate content in slow and fast growing chicken and in chickens with heart failure and ascites

In order to explain the biochemical mechanisms associated with deteriorating heart function in broiler chickens, this study compared myocardial high energy phosphate substrates in leghorns, feed restricted (Broilers-Res) broilers, ad libitum fed broilers (Broilers-AL), and in broilers that developed heart failure and ascites. The profile of adenine nucleotide content in the heart tissue did not differ between leghorns and Broilers-Res, but there were significant differences among Broilers-Res, Broilers-AL, and broilers with ascites. During intensive growth periods, leghorns and Broilers-Res showed increasing trends in heart ATP levels, whereas in fast growing broilers the heart ATP declined (p<0.021). ATP:ADP and ATP:CrP ratios increased with age in both leghorn and Broilers-Res, declined in fast growing broilers, and were the lowest in broilers that developed heart failure. The changes in heart high energy phosphate profile in broilers suggest that the energy demand of the heart during a rapid growth phase may exceed the bird's metabolic capacity to supply adequate levels of high energy phosphate substrate. The insufficiency of energy substrate likely contributes to the declining heart rate. In some individuals this may lead to impaired heart pump function, and in more severe cases may progress to heart pump failure.     

Joint dynamic imaging of morphogenesis and function in the developing heart

In the developing heart, time-lapse imaging is particularly challenging. Changes in heart morphology due to tissue growth or long-term reorganization are difficult to follow because they are much subtler than the rapid shape changes induced by the heartbeat. Therefore, imaging heart development usually requires slowing or stopping the heart. This, however, leads to information loss about the unperturbed heart shape and the dynamics of heart function. To overcome this limitation, we have developed a non-invasive heart imaging technique to jointly document heart function (at fixed stages of development) as well as its morphogenesis (at any fixed phase in the heartbeat) that does not require stopping or slowing the heart. We review the challenges for imaging heart development and our methodology, which is based on computationally combining and analyzing multiple high-speed image sequences acquired throughout the course of development. We present results obtained in the developing zebrafish heart. Image analysis of the acquired data yielded blood flow velocity maps and made it possible to follow the relative movement of individual cells over several hours.Key words: cardiac imaging, zebrafish, fluorescence imaging, heart development, registration, fast imaging     

Atrial natriuretic factor alters autonomic interactions in the control of heart rate in conscious rats

Regulation of heart rate was studied in rats receiving either i.v. saline at 64 microL/min or synthetic 28-residue rat atrial natriuretic peptide (ANF) at a dose sufficient to decrease mean arterial blood pressure by 10%. Autonomic influences were deduced from steady-state heart rate responses of each group to propranolol, atropine, or propranolol and atropine combined. A multiplicative model of heart rate control was used to derive quantitatively from the data the modulation of intrinsic heart rate by sympathetic and parasympathetic mechanisms. Animals receiving ANF showed a lower heart rate than control animals. This relative bradycardia was abolished by atropine. Blocking of sympathetic effects with propranolol had no effect on basal heart rate in either group, and atropinization led to significant increases in heart rate in both groups of rats. Mathematical analysis of the results showed that the bradycardia produced by ANF was due predominantly to a reduced intrinsic heart rate and to enhanced vagal inhibition of postganglionic sympathetic activity. Parasympathetic contribution to heart rate in the absence of sympathetic activity was negligible in control rats and small during ANF. We conclude that the major influences of ANF on heart rate control are a decrease of intrinsic heart rate and enhanced parasympathetic inhibition of postganglionic presynaptic sympathetic activity.     

用心率变异功率谱研究出生后心率变慢的机理

目的 :探讨神经机制及心源性因素在出生后心率变慢中的作用。方法 :运用心率变异性的频域和时域分析方法 ,主要为功率谱分析方法 ,以不同年龄组的人和家兔为实验对象 ,对出生后心脏的自主神经调控进行初步探讨 ;并通过观察不同年龄组离体灌流兔心 (无神经体液因素影响 )自律性的变化 ,探讨心脏本身因素是否参与出生后心率变慢的调控。结果 :人和家兔迷走交感对心率的调控作用比在各年龄组之间有显著差异 ,且随年龄增长逐渐升高 ;家兔离体心脏的自主心率在各年龄组之间有显著差异 ,且随年龄增长逐渐降低。结论 :出生后心率减慢与神经机制有关 ,也有心脏本身因素的参与     

Spectral analysis of heart sounds: Relationships between some physical characteristics and frequency spectra of first and second heart sounds in normals and hypertensives

Frequency analysis of heart sounds has been gaining recognition as a possible indicator of several heart and valve diseases, although a comprehensive study of normal heart sounds has not been published. Relating the frequency content of normal heart sounds to certain physical characteristics surrounding the generation of these sounds could lead to a valuable diagnostic tool and give a better understanding of the mechanism of heart sounds production. In this study, the first and second heart sounds from seventy-four normal, and seven hypertensive volunteers were recorded, digitized and analysed using a Fast Fourier Transform algorithm. Statistical analysis was used to relate physical characteristicss (sex, blood pressure, and body surface area) of the subjects to the frequency content of normal heart sounds and to compare normal and hypertensive heart sounds. Statistical analysis showed that the major concentration of energy, for both first heart sound (S1) and second heart sound (S2), is below 150 Hertz (Hz) which may indicate that both sounds are caused by vibrations within the same structure, possibly the entire heart. However S2 spectra have greater amplitude than S1 spectra above 150 Hz, which may be due to vibrations within the aorta and pulmonary artery. Relationships observed between body surface area, sex, blood pressure, and the frequency content of heart sounds indicate that as heart size increases, the amplitude of the frequency coefficients above 150 Hz decreases. These observations were more identifiable in the S1 spectra than in the S2 spectra, possibly because the S2 higher frequency components may mask subtle changes in the S2 spectra caused by heart size changes. However, when the changes in heart size are significant, as in hypertension or increased body surface area, trends in the S2 spectra can be observed.     

Catecholamine-induced cardiac hypertrophy in a denervated,hemodynamically non-stressed heart transplant

Studies of stress-induced cardiac hypertrophy suggest that myocardial mass is regulated by the circulating level of epinephrine. The trophic effect is mediated by cardiac beta-adrenergic receptors, and in the murine, rat, and dog heart, specifically by beta₂-adrenergic receptors. The well-characterized functional effects of catecholamines on heart have obscured their role as myocardial trophic hormones. Therefore, we compared the effect of beta-adrenergic receptor stimulation on the myocardial mass of both a working innervated heart and an essentially nonworking denervated heterotopically transplanted heart in the same rat; in this model, the neural and stretch parameters are nonoperational in the transplanted heart. Ornithine decarboxylase (ODC), an enzyme elevated in a dose-dependent manner in heart by isoproterenol, was assayed in both hearts to determine the relationship between ODC activity and myocardial mass in response to isoproterenol administration in workin, innervated heart compared to denervated, nonworking heart. In both recipient and donor heart, the myocardial mass paralleled the ability of an isoproterenol bolus to stimulate ODC in the respective heart. However, beta-adrenergic receptor activity in the donor heart was decreased 5 days after transplantation as assessed by the differential ability of a single dose of isoproterenol to stimulate ODC activity. Beta-receptor coupling to ODC activity in the donor heart exceeded that of the recipient heart at 10 days posttransplantation suggesting a time-dependent elevation of beta-adrenergic receptor activity in donor heart. At all times, alterations in myocardial mass paralleled beta-adrenoceptor activity as assessed by the ability of isoproterenol administration to elevate ODC activity. The results support the concept that myocardial mass is regulated by the level of circulating hormones, particularly epinephrine.     

Individual differences in motor skills ability affect the self-regulation of heart rate

Twenty males who scored relatively high on the rotor-pursuit motor skills task (High performance group) were given seven 2-minute trials to increase heart rate and seven 2-minute trials to decrease heart rate, as were 20 males who scored relatively low on the rotor-pursuit task (Low performance group). Visual analogue feedback was not provided during the first and last acceleration and deceleration trials but was presented during all other trials. Both groups of subjects were able to decrease heart rate significantly with and without feedback. Subjects in the High performance group were able to increase heart rate significantly with feedback and could generalize this increase to a no-feedback trial following feedback trials. Subjects in the Low performance group could not increase heart rate with or without feedback. Changes in respiration rate paralleled those noted for heart rate, but changes in chin electromyographic activity generally did not parallel the heart rate results. The heart rate data are discussed in terms of motor skills theories of self-regulation of heart rate.     

Effects of Biofeedback Training on Voluntary Heart Rate Control During Dynamic Exercise

The aims of this study were to (1) compare the effect of biofeedback with that of verbal instructions on the control of heart rate during exercise on a treadmill, (2) test the possible effect of workload on this control, and (3) examine the effect of workload on baseline heart rate at rest and during exercise. The study involved 35 participants who were randomly assigned to each of 4 experimental conditions generated by combining the 2 independent variables: training strategy for heart rate control (heart rate biofeedback or verbal control instructions) and work level (30 or 50% of maximal heart rate). By the end of 5 experimental sessions, participants trained with heart rate biofeedback showed a greater attenuation of the increase in heart rate produced by exercise than participants trained with verbal control instructions. The workload did not influence the voluntary control of heart rate, nor did it affect resting baseline heart rate, but it did affect exercise baseline heart rate.     

单细胞转录组测序技术在心脏发育、疾病以及医学中的 应用

单细胞转录组测序(Single-cell RNA sequencing,scRNA-seq)可以在单细胞水平描绘出每个细胞同一基因的表达量在不同细胞间的表达水平差异,使得在单细胞水平重新认识各种组织器官成为可能.目前对心脏的测序研究正从传统的普通转录组水平过渡到单细胞水平,对小鼠和人的心脏的测序陆续地发表出来.概述了s...