The heart in higher vertebrates develops from a simple tube into a complex organ with four chambers specialized for efficient pumping at pressure. During this period, there is a concomitant change in the level of myocardial organization. One important event is the emergence of trabeculations in the luminal layers of the ventricles, a feature which enables the myocardium to increase its mass in the absence of any discrete coronary circulation. In subsequent development, this trabecular layer becomes solidified in its deeper part, thus increasing the compact component of the ventricular myocardium. The remaining layer adjacent to the ventricular lumen retains its trabeculations, with patterns which are both ventricle- and species-specific. During ontogenesis, the compact layer is initially only a few cells thick, but gradually develops a multilayered spiral architecture. A similar process can be charted in the atrial myocardium, where the luminal trabeculations become the pectinate muscles. Their extent then provides the best guide for distinguishing intrinsically the morphologically right from the left atrium. We review the variations of these processes during the development of the human heart and hearts from commonly used laboratory species (chick, mouse, and rat). Comparison with hearts from lower vertebrates is also provided. Despite some variations, such as the final pattern of papillary or pectinate muscles, the hearts observe the same biomechanical rules, and thus share many common points. The functional importance of myocardial organization is demonstrated by lethality of mouse mutants with perturbed myocardial architecture. We conclude that experimental studies uncovering the rules of myocardial assembly are relevant for the full understanding of development of the human heart.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/%28SICI%291097-0185%2820000401%29258%3A4%3C319%3A%3AAID-AR1%3E3.0.CO%3B2-O

Developmental patterning of the myocardium.

Body mass, length, oxygen consumption (M˙o 2) and heart rate (f H) were measured in “embryos” (prior to hatching), “larvae” (days 10–20), “juveniles” (days 30–70 in 10-day intervals), and “adults” ...

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O2 consumption and heart rate in developing zebrafish (Danio rerio): influence of temperature and ambient O2

The pathogenesis of many congenital cardiovascular diseases involves abnormal flow within the embryonic vasculature that results either from malformations of the heart or defects in the vasculature itself. Extensive genetic and genomic analysis in mice has led to the identification of an array of mutations that result in cardiovascular defects during embryogenesis. Many of these mutations cause secondary effects within the vasculature that are thought to arise because of altered fluid dynamics. Presumably, cardiac defects disturb or reduce flow and thereby lead to the disruption of the mechanical signals necessary for proper vascular development. Unfortunately, a precise understanding of how flow disruptions lead to secondary vasculature defects has been hampered by the inadequacy of existing analytical tools. Here, we used a fast line-scanning technique for the quantitative analysis of hemodynamics during early organogenesis in mouse embryos, and we present a model system for studying cellular responses during the formation and remodeling of the mammalian cardiovascular system. Flow velocity profiles can be measured as soon as a heart begins to beat even in newly formed vessels. These studies establish a link between the pattern of blood flow within the vasculature and the stage of heart development and also enable analysis of the influence of mechanical forces during development.

Measuring hemodynamic changes during mammalian development

Hypoxic states of the cardiovascular system are undoubtedly associated with the most frequent diseases of modern times. They originate as a result of disproportion between the amount of oxygen supplied to the cardiac cell and the amount actually required by the cell. The degree of hypoxic injury depends not only on the intensity and duration of the hypoxic stimulus, but also on the level of cardiac tolerance to oxygen deprivation. This variable changes significantly during phylogenetic and ontogenetic development. The heart of an adult poikilotherm is significantly more resistant as compared with that of the homeotherms. Similarly, the immature homeothermic heart is more resistant than the adult, possibly as a consequence of its greater capability for anaerobic glycolysis. Tolerance of the adult myocardium to oxygen deprivation may be increased by pharmacological intervention, adaptation to chronic hypoxia, or preconditioning. Because the immature heart is significantly more dependent on transsarcolemmal calcium entry to support contraction, the pharmacological protection achieved with drugs that interfere with calcium handling is markedly altered. Developing hearts demonstrated a greater sensitivity to calcium channel antagonists; a dose that induces only a small negative inotropic effect in adult rats stops the neonatal heart completely. Adaptation to chronic hypoxia results in similarly enhanced cardiac resistance in animals exposed to hypoxia either immediately after birth or in adulthood. Moreover, decreasing tolerance to ischemia during early postnatal life is counteracted by the development of endogenous protection; preconditioning failed to improve ischemic tolerance just after birth, but it developed during the early postnatal period. Basic knowledge of the possible improvements of immature heart tolerance to oxygen deprivation may contribute to the design of therapeutic strategies for both pediatric cardiology and cardiac surgery.

https://www.physiology.org/doi/pdf/10.1152/physrev.1999.79.3.635

Development of Cardiac Sensitivity to Oxygen Deficiency: Comparative and Ontogenetic Aspects

Little is known about the sensitivity of Antarctic krill, a key part of the food chain, to ocean acidification. A circumpolar risk map of krill hatching success is presented for projected ocean acidification levels. Important krill recruitment habitats are likely to become high-risk this century, with the possibility of collapse of the krill population by 2300 without mitigation of CO2 emissions.

Risk maps for Antarctic krill under projected Southern Ocean acidification

The concept of animal models is well honored, and amphibians have played a prominent part in the success of using key species to discover new information about all animals. As animal models, amphibians offer several advantages that include a well-understood basic physiology, a taxonomic diversity well suited to comparative studies, tolerance to temperature and oxygen variation, and a greater similarity to humans than many other currently popular animal models. Amphibians now account for approximately 1/4 to 1/3 of lower vertebrate and invertebrate research, and this proportion is especially true in physiological research, as evident from the high profile of amphibians as animal models in Nobel Prize research. Currently, amphibians play prominent roles in research in the physiology of musculoskeletal, cardiovascular, renal, respiratory, reproductive, and sensory systems. Amphibians are also used extensively in physiological studies aimed at generating new insights in evolutionary biology, especially in the investigation of the evolution of air breathing and terrestriality. Environmental physiology also utilizes amphibians, ranging from studies of cryoprotectants for tissue preservation to physiological reactions to hypergravity and space exploration. Amphibians are also playing a key role in studies of environmental endocrine disruptors that are having disproportionately large effects on amphibian populations and where specific species can serve as sentinel species for environmental pollution. Finally, amphibian genera such as Xenopus, a genus relatively well understood metabolically and physiologically, will continue to contribute increasingly in this new era of systems biology and "X-omics."

Amphibians as Animal Models for Laboratory Research in Physiology

The heart beat of vertebrate embryos has been assumed to begin when convective bulk transport by blood takes over from transport by simple diffusion. To test this hypothesis, we measured eye growth, cervical flexure and rates of oxygen consumption ( V(O2)) in day 3-4 chick embryos denied cardiac output by ligation of the outflow tract and compared them with those of embryos with an intact cardiovascular system. Eye diameter, used as the index for embryonic growth, increased at a rate of approximately 4.5-5 % h(-)(1) during the observation period. There was no significant difference (P>0.1) in the rate of increase in eye diameter between control (egg opened), sham-ligated (ligature present but not tied) and ligated embryos. Similarly, the normal progression of cervical flexure was not significantly altered by ligation (P>0.1). V(O2) (ml O(2 )g(-)(1 )h(-)(1)) at 38 degrees C, measured by closed respirometry, was not significantly different (P>0.1) on day 3 in sham-ligated (14.5+/-1.9 ml O(2 )g(-)(1 )h(-)(1)) and ligated 17.6+/-1.8 ml O(2 )g(-)(1 )h(-)(1)) embryos. Similarly, on day 4, V(O2) in sham-ligated and ligated embryos was statistically the same (sham-ligated 10. 5+/-2.9 ml O(2 )g(-)(1 )h(-)(1); ligated 9.7+/-2.9 ml O(2 )g(-)(1 )h(-)(1)). Expressed as a linear function of body mass (M), V(O2) in sham-ligated embryos was described by the equation V(O2)=-0.48M+24.06 (r(2)=0.36, N=18, P<0.01), while V(O2) in ligated embryos was described by the equation V(O2)=-0.53M+23.32 (r(2)=0.38, N=16, P<0.01). The regression line describing the relationship between body mass and V(O2) for pooled sham-ligated and ligated embryos (the two populations being statistically identical) was V(O2)=-0.47M+23.24. The slope of this regression line, which was significantly different from zero (r(2)=0.30, N=34, P<0.01), was similar to slopes calculated from previous studies over the same range of body mass.Collectively, these data indicate that growth and V(O2) are not dependent upon cardiac output and the convective blood flow it generates. Thus, early chick embryos join those of the zebrafish, clawed frog and axolotl in developing a heart beat and blood flow hours or days before required for convective oxygen and nutrient transport. We speculate that angiogenesis is the most likely role for the early development of a heart beat in vertebrate embryos.

Interruption of cardiac output does not affect short-term growth and metabolic rate in day 3 and 4 chick embryos.

Although most research on developmental cardiovascular physiology has focused on the bird embryo as a model for emulating developmental processes in mammals, there are increasingly compelling reasons to expand research to a variety of lower vertebrate systems. These reasons include circumventing inherent limitations of the avian embryo and identifying general vertebrate developmental patterns in the cardiovascular system. In this paper, we first review data from hemodynamic studies on amphibians and birds (and what little exists from fish and reptiles), to provide a background against which lower vertebrate development can be examined. We then describe non-mammalian, non-avian paradigms for studying developmental patterns of vertebrate hearts. Developmental spects of cardiovascular performance, especially heart rate, blood pressure and cardiac output and how they change with ontogeny, are described for several amphibians and a few reptiles, identifying, where possible, processes in common with birds and mammals. Finally, we indicate productive areas for future research with lower vertebrate cardiovascular systems, such as establishing "critical windows" for cardiovascular physiology during development, and determining the extent of developmental plasticity at the level of organ system physiology.

Patterns of form and function in developing hearts: contributions from non-mammalian vertebrates.

▪ Abstract Comparative developmental physiology spans genomics to physiological ecology and evolution. Although not a new discipline, comparative developmental physiology's position at the convergence of development, physiology and evolution gives it prominent new significance. The contributions of this discipline may be particularly influential as physiologists expand beyond genomics to a true systems synthesis, integrating molecular through organ function in multiple organ systems. This review considers how developing physiological systems are directed by genes yet respond to environment and how these characteristics both constrain and enable evolution of physiological characters. Experimental approaches and methodologies of comparative developmental physiology include studying event sequences (heterochrony and heterokairy), describing the onset and progression of physiological regulation, exploiting scaling, expanding the list of animal models, using genetic engineering, and capitalizing on new miniatu...

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COMPARATIVE DEVELOPMENTAL PHYSIOLOGY:An Interdisciplinary Convergence

The regulation of arterial pressure in early vertebrate embryos and larvae with non-innervated hearts is poorly understood. We used nanoliter intravascular injections in anaesthetized Xenopus laevis larvae (stage 49–51) to assess their ability to maintain arterial pressure in the face of a volume load. Injections of saline and hetastarch (a volume expander) were made into the ventricle. Arterial pressure, end-diastolic ventricular volume, end-systolic ventricular volume and heart rate were measured. Injection of 800 nl caused a rapid rise in arterial pressure and stroke volume. There were no changes in heart rate, indicating the absence of an arterial baroreflex. Blood pressure in saline-injected animals recovered quickly (within 5 min), whereas hetastarch injections caused hypertension to be maintained for much longer, for over 40 min in the most extreme case. We surmise that Starling forces at the capillary play an important role in pressure regulation but are not adequate to explain the entire response. Finally, there was ample evidence for a Frank-Starling relationship in the ventricle.

Stephen Warburton

Papers

Amphibians as Animal Models for Laboratory Research in Physiology

Interruption of cardiac output does not affect short-term growth and metabolic rate in day 3 and 4 chick embryos.

Patterns of form and function in developing hearts: contributions from non-mammalian vertebrates.

COMPARATIVE DEVELOPMENTAL PHYSIOLOGY:An Interdisciplinary Convergence

Blood pressure control in a larval amphibian, Xenopus laevis.