15.1 Introduction

As we learned in the previous chapter, gas exchange is pretty darn important. All our cells need oxygen and nutrients, and they need waste products to be removed. It doesn’t take long, developmentally speaking, for vertebrates to reach a size where simple diffusion is no longer sufficient and where a circulatory system is necessary to move things around the body. Those things are not just oxygen and carbon dioxide but also nutrients, hormones, chemicals, metabolic waste products, and cells. In other words, a blood draw can tell your physician an awful lot about your health because blood does so much for your cells.

15.2 Structure and Function

At the most basic level, the vertebrate circulatory system is composed of three components: a fluid to carry everything we need to move around the body, the pipes that carry the fluid, and the pump that moves the fluid through the pipes. Even though they’re part of the same system, we often divide the circulatory system into two components:

1. The blood circulation: blood (fluid), blood vessels (pipes), and heart (pump)
2. The lymphatic circulation: lymph (fluid), lymphatic vessels (pipes), and heart (pump)

This chapter will mostly focus on blood circulation, but we will discuss lymphatic circulation at several points.

The Fluid: Blood

Blood is composed of both solids and a liquid component called plasma. Plasma is largely water with a bunch of stuff dissolved in it, including gases, glucose, hormones, proteins, various clotting factors, and ions. In humans, plasma is responsible for just over half of your blood volume. The solid component of the blood is often called the formed elements, as they are cells that are formed in other organs, such as the bone marrow or spleen, and then make their way to the bloodstream via gaps in certain types of capillaries (see Box 15.1). We know these cells as erythrocytes (red blood cells), leukocytes (white blood cells), and thrombocytes (platelets). The erythrocytes carry oxygen around the body. Leukocytes are broadly involved in the immune system, both as a first line of defense and as part of a body’s long-term defense against potential pathogens. Thrombocytes form a key component of the clotting response, helping close wounds to prevent further loss of blood.

The Pipes: Vessels

Now we need a way to move that fluid around. Vertebrate blood circulation moves through a closed circulatory system, which means that the pipes never empty into anything but the heart—it’s a closed system unless a vessel is damaged and you start bleeding. This is something that has independently evolved in a few other animals, including cephalopods (octopus, squid, and cuttlefish). Nonvertebrate chordates, like several other invertebrates, have an open circulatory system. A pump moves fluid through vessels that eventually empty into a cavity; the fluid then moves back to the heart thanks to the pressure of more fluid being added to the cavity. A major advantage of the closed circulatory system is the ability to preferentially direct blood flow to different tissues (by changes of vascular resistance) in response to changes in metabolic demand—for example, during digestion (during which blood flow can be prioritized to the gastrointestinal circulation) or during physical exertion, when blood flow is diverted to skeletal muscle.

Let’s take a closer look at those pipes. We can first divide them up by size, into arteries, veins, and microcirculation (Figure 15.1). Arteries carry blood away from the heart, while veins carry blood toward the heart. Note that we did not connect either type of vessel to the oxygenation status of the blood; whether arteries (or veins) carry oxygen-rich or oxygen-poor blood depends on where in the circulation you are and which vertebrate you’re examining. We’ll get to that later.

Both arteries and veins are made of the same layers (Figure 15.2). The outermost layer is called the tunica adventitia (sometimes also called the tunica externa), which is mostly connective tissue. The next layer is the tunica media, which is a combination of smooth muscle and elastic fibers. The ratio of these varies; veins tend to contain very few elastic fibers, and arteries tend to contain a lot of elastic fibers to deal with the pulse of pressure from the heart. The innermost layer is called the tunica intima, which is composed of a layer of endothelial cells. The open center of the vessel, where the blood flows, is called the lumen.

The microcirculation is composed of arterioles, capillaries, and venules, and as the name implies, these are the vessels that are not visible to the naked eye. Arterioles and venules are very small arteries and veins, respectively. Capillaries are the smallest blood vessels and only have a tunica intima and lumen. Having this single, thin layer is important because capillaries are the sites where materials can move in and out of the blood in exchange with the nearby cells.

Box 15.1—Leaky Capillaries

Capillaries are generally classified by how leaky they are (Figure 15.3). All capillaries are a little leaky because of the pressure of blood being pushed from the arterioles. This causes some of the liquid components of blood to leak out of the capillaries. When that liquid leaves the capillaries, it joins the interstitial fluid bathing your cells and tissues. Continuous capillaries (sometimes also called “closed capillaries”) lose only a little bit of liquid and allow only small molecules to move through their walls. However, fenestrated capillaries have larger openings to allow some proteins to also move through. Sinusoidal capillaries have the largest openings and are thus the leakiest, allowing blood cells to pass. How leaky a capillary is, and thus the type of capillary you find at a particular organ, depends on the needs of the cells they serve. Knowing what you do about different tissues and organs so far, hypothesize about an organ that would need each type of capillary and why. Then do some research to find out if you were correct!

Let’s put our circulatory system together so far. Arteries move blood away from the heart. The largest arteries come straight off the heart and then split into smaller and smaller arteries, much as a building may have one pipe receiving water from a city, and then that pipe splits into smaller and smaller pipes to serve each room of the building. Eventually, the arteries divide into arterioles, which divide into capillaries. Capillaries merge into venules, which merge into veins, returning blood back to the heart.

The Pump: Heart

Now that we understand the pipes and the fluid within the pipes, we need to examine how that fluid is moved through the pipes. The heart is a ventrally located muscular tube that pushes the fluid into the pipes by contracting and creating positive pressure but also brings fluid into the heart by creating negative pressure that pulls fluid in. As we examine different vertebrates later in this chapter, we will see that hearts vary in terms of the number of chambers in that tube and how they’re arranged. However, regardless of the vertebrate, blood enters the heart cranially and leaves it caudally. The vessels are in charge of moving the blood in a different direction after it leaves the heart.

When the heart contracts and produces the highest positive pressure, it is in systole. When the heart muscle relaxes and produces its lowest pressure, it is in diastole. When a medical professional measures blood pressure, they give two numbers. The higher number is the systolic pressure, and the lower number is the diastolic pressure. These are often reported together (e.g., “120 over 80”) and are reported in mm Hg as the unit.

The positive pressure created by the heart as it contracts is at its highest in the artery (arteries) immediately leaving the heart (Figure 15.4). In humans, the aorta is the artery that sends blood out of the body to drop off oxygen to its cells and pick up carbon dioxide waste; the pressure is about 130 mm Hg (about 2.5 psi) within the aorta. As we move through the arteries as they split and split into smaller and smaller vessels, blood pressure drops the farther we move away from the heart. Part of this pressure drop is due to the friction between the blood vessel walls and the blood. However, we’re also distributing that blood volume among many small pipes/vessels. Our building water main analogy is useful here again. The pressure coming out of a single faucet is much lower than that out of the pipe bringing water to the building.

The blood vessels, however, are not rigid. Arterioles and veins can change much in diameter due to the contraction or relaxation of smooth muscle cells in their walls. If arterioles in the skin expand in diameter, as can happen when you are heating up, then the resistance to blood flow decreases in this part of the circulatory system, and blood flow increases to the skin. This can facilitate cooling down. Heating up the body can happen as a consequence of exercise. During exercise, a high number of arterioles in the active musculature dilate while veins may constrict under the influence of the nervous system. The cumulative effect of this is that a substantial fraction of the total blood volume is shifted from the veins to other elements of the systemic circulation. This helps maintain blood pressure, if not increase it.

By the time we get to the capillaries, the pressure has dropped to about 20 mm Hg (about 0.4 psi) in humans. Pressure continues to drop as we move through the venules (12 mm Hg in humans) and veins (5 mm Hg in humans, to almost 0 mm Hg in some large veins) and head back to the heart. Pressure in these large veins can sometimes drop below 0 mm Hg; to prevent blood from moving backward during negative pressure, veins are equipped with one-way valves that prevent backward flow. Some large veins also receive an assist from the adjacent skeletal muscle. When those muscles contract, they squeeze the veins, providing a boost to the blood back toward the heart. This is why during long periods of sitting, such as a long airplane flight, it is important to move your legs to help that venous blood along.

Lymphatic Circulation: Our Second Set of Pipes

We have one more set of pipes to worry about. Recall that all capillaries are leaky and that some plasma will join the interstitial fluid. This fluid needs to be returned to the vascular system. Much of that happens right at the capillaries thanks to osmotic pressure. However, not all the lost fluid is returned, and this is where the lymphatic circulation contributes.

Lymphatic capillaries are often found in conjunction with the blood capillaries (Figure 15.5). Like blood capillaries, lymph capillaries are very small and thin walled. Unlike blood capillaries, they are blind-ended. The interstitial fluid enters through openings called buttons between the endothelial cells to allow fluid and immune cells to enter. When interstitial fluid enters the lymphatic vessels, it is called lymph and has a similar composition to blood plasma.

Lymphatic capillaries have a small layer of smooth muscle that can contract to help move lymph from the capillaries into the lymphatic vessels. Lymphatic vessels have a similar organization to blood vessels—they have a tunica intima, media, and adventitia. Like veins, the lymphatic vessels operate under low pressure and need some help. Pressure is generated by that smooth muscle as well as the surrounding skeletal muscles and nearby pulsing arteries. And like veins, lymphatic vessels have unidirectional valves that prevent backflow. So how does that lymph eventually make it back into the blood? Eventually, the large lymphatic vessels connect to veins near the heart and return the filtered fluid to the blood. Some vertebrates (amphibians and nonavian reptiles) have lymphatic hearts that help create more pressure to get that lymph back into the bloodstream.

In addition, the lymphatic system is also part of the immune system. Lymphatic tissue, also known as lymphoid organs, are sites of immune cell production and maturation (Figure 15.6). These include the bone marrow, thymus, spleen, appendix, tonsils, lymph nodes, and lymphatic cisterns or sacs. Not all vertebrates have all these structures. For example, lymph nodes are strictly a mammal and occasional bird feature. Lymph nodes are in line with the lymph vessels, receiving lymph from lymph vessels. The interior of the lymph node is composed of a series of sinuses that allow macrophages to remove antigens and dead cells from the lymph before the lymph returns to blood circulation.

15.3 Morphological Development

The development of the heart and the blood vessels is inherently intertwined. They are among the first structures to form during development, as their role in moving materials around the body is crucial for the development of other body systems. Consider the entire circulatory system as one large tube, interconnected with many different subdivisions and mergers. Once the general “tube” is in place, then it is just a matter of how the tubes grow, twist, and shape themselves that will help distinguish the different structures that come together to form the entire system.

Most circulatory system elements are derived from mesoderm and cardiac neural crest cells. The original pieces of the blood vessel network are stem-endothelial cells, cells that will eventually line the interior of all blood vessels and the heart. Now, these early stages are quite complicated, but we can simplify things for our purposes. At the same time, these endothelial cells are forming and migrating, and precursors of red blood cells are also forming. Through genetic and chemical signaling, the endothelial cells wrap around pockets of the developing blood cells. Imagine there are many of the pockets forming in the developing embryo. As they encounter one another, they will merge (anastomose, in blood vessel terminology), gradually forming larger and larger networks. At this point, we can now refer to these growing networks as capillaries. New vessels forming this way can be referred to as vasculogenesis, the origin of blood vessels without other preexisting blood vessels. As the networks grow larger and larger, they will connect to one another. Larger vessels will differentiate into arteries and veins; smaller vessels will remain as capillaries. When these different vessels have formed, new vessels will develop and may connect them together. The formation of new vessels (throughout the entire life of an individual) from existing vessels is known as angiogenesis.

The embryological development of the heart provides an informative background to understand the structures in the adult heart and the blood vessels. This process takes place within the cardiopharyngeal field. In addition to the heart, and as implied by its name, the cardiopharyngeal field also gives rise to the lungs and craniofacial features.

The part of the cardiopharyngeal field that develops into the myocardium folds in on itself and forms a heart tube. The heart tube is a straight tube oriented parallel to the embryo’s long axis and has a solitary venous pole and a solitary arterial pole (Figure 15.6). Some species, such as zebrafish, deviate from this pattern and first form a cardiac disk. The disk then extrudes itself to become a tube. In doing so, it comes to lie at a skewed angle relative to the embryo’s long axis, and this process is referred to as “jogging.” Jogging leaves the venous pole of the heart tube to the left of the body midline, and this is the earliest example of a morphological break with left-right symmetry in zebrafish development. The endocardium lines the inside of the heart tube and separates the lumen from the myocardium. The endocardium also connects with the endothelium of the developing arteries and veins. In this sense, the heart of the early embryo appears as a modified blood vessel, and blood vessels are phylogenetically much older than the heart.

Later in development, the straight heart tube loops, and its topology now becomes asymmetrical relative to all three principal anatomical planes. By default, the heart is looped in a counterclockwise fashion, if we were to view it from a caudal position. Importantly, the looping sets the stage for where chambers develop and thus the topology of the formed heart (Figure 15.7). In humans and chickens, the processes of heart tube formation and subsequent looping are distinct, whereas they occur simultaneously in mice. Also, the length of the heart tube and its degree of looping vary between clades. While modest looping occurs in zebrafish and Adriatic sturgeon, in lungfishes, looping well in excess of 360 degrees occurs. The formed lungfish heart has a very long outflow tract that turns some 270 degrees, and the embryonic heart tube formation and looping appear to set the stage for this.

Activity of transcriptional networks is required for the formation and looping of the heart tube as well as the development of chambers. Transcription factors (proteins that influence gene activity) are key components of these networks, and so are growth factors and more. These also induce the formation of cushions of mesenchyme, or connective tissue. Cushions form versatile scaffolds that give rise to the atrioventricular and arterial valve leaflets. They can also set the stage for atrial and ventricular septation and contribute to the final closure of interatrial and interventricular communication in tetrapods. In addition, two long cushions or ridges can contribute to separate oxygen-poor and oxygen-rich blood, as in the African lungfishes. In amniotes the outflow tract cushions merge to separate the pulmonary trunk from the systemic channel. This particular division requires not only mesenchymal tissues but also immigrating neural crest cells.

After the heart has taken its final shape, it will continue to grow as the individual does. Parts of the myocardium may become so thick that a dedicated vasculature is required. This could be the conus arteriosus or the ventricular wall. There, coronary vessels develop via angiogenesis, and they grow across these parts of the heart, becoming conduits for oxygenated blood to the myocardium. Thin parts of the myocardium, which could be trabeculations or walls of veins, remain homeostatic for the most part by exchange by diffusion from luminal blood.

15.4 Evolution and Diversity

Before we walk through the details of the evolution of the various circulatory system components, we should first get a general idea of the blood circulatory pathways in various extant vertebrate groups.

The cyclostomes, chondrichthyans, and teleosts follow a similar general circulatory plan (Figure 15.8). Oxygen-poor blood travels from the heart to the gills via arteries, where oxygen enters the blood and carbon dioxide leaves the blood across the gill epithelium. In Chapter 14, we discussed that gills are also responsible for the movement of ions in or out of the blood plasma. The newly oxygenated blood is distributed through arteries after the gills to all cells of the body, where a second capillary bed enables gas exchange in the tissues. Oxygen-poor blood then returns to the heart to undergo another circuit.

During the transition from water to land, there are a few major changes that occur in lineages leading to the tetrapods as well as throughout the tetrapods. The respiratory and circulatory systems are tightly coupled. Changes in the mode of respiration necessitate changes to the circulatory system. To varying extents, this means that instead of one single circuit of blood in the fish heart (Figure 15.8), we get a double circulatory system where oxygenated blood from the lungs is returned to the heart (Figure 15.9). The pulmonary circuit refers to the pulmonary arteries that bring blood from the heart to the lungs and the pulmonary veins that return oxygenated blood to the heart. The systemic circuit consists of all the blood vessels that supply the remainder of the body. The transition from a single circulatory circuit to a double circuit is going to require us to walk through some developmental and functional changes.

The structure of the heart and major arteries shows the most taxonomic variation across the vertebrates and so will be the focus of the sections below, although peripheral vascular adaptations will also be highlighted where relevant.

Arches and Vasculature

All blood leaving the heart, across all vertebrates, leaves through one large vessel that we refer to as the aorta (Figure 15.9). However, once that blood enters the aorta, the path it travels varies considerably in our vertebrate groups. Some of these changes are concurrent with changes that are occurring with the already mentioned changes in respiration (see Chapter 14—Respiratory System) and the changes to the structure of the heart (see the subhead Hearts). To begin, let us build a schematic that will serve to orient us to the arches (Figure 15.10). There are six aortic arches (AA) in this developing embryo, with the first pair being the most cranial. These six arches arise from the ventral aorta and then travel to the dorsal aorta. If we return to the general plumbing schematics above, we can already get a feel for how blood moves through this system. Blood enters the ventral aorta from the heart. As the blood travels through the ventral aorta, some of the volume will be diverted at each passing arch. As the blood passes through each arch, in a vertebrate like the dogfish shark, the blood will be oxygenated through the gills. It will then pass into the dorsal aorta and through to the rest of the body. By working our way through the vertebrate lineages, we can track the fate of the six aortic arches and closely examine how these changes correspond to body-wide changes in other systems.

The branchial arches in invertebrate chordates primarily serve for filter feeding and/or ion regulation, but they play a pivotal role in gas exchange in cyclostomes and probably also in the early vertebrates.

Cyclostomes, the jawless hagfish and lamprey, while having a similar schematic of aortic arches as described above, vary widely in the number of arches. Lamprey may have 6 or 7 arches, and hagfishes have anywhere from 6 to as many as 15. In all cases, the aortic arches are associated with the pharyngeal arches, which contain the gill arches. The cartilaginous fishes widely share a similar pattern, although the fate of the arches now begins to change. In the sharks, the skeletal elements of arch 1 are going to become the jaws (Figure 15.11). The blood vessels that would be associated with that arch (aortic arch 1) are also going to be modified. While not completely traveling with the skeletal elements, aortic arch 1 (AA 1) is now going to be associated with the spiracle, an accessory respiratory structure, but is not a site for gas exchange. AA 2–6 are still going to be associated with gill arches, going through gas exchange and providing oxygen to the other body tissues.

It is in the bony fishes (Osteichthyes) that the aortic arches start to become more heavily modified. Developmentally, all six arches appear in a sequential pattern, seemingly unmodified. However, as development progresses, changes to the musculoskeletal framework (and respiratory system) are tightly correlated with the changes that we will observe in the arches. In the teleost fishes, AA 1 and 2 are lost functionally as sites of gas exchange. They instead contribute to the mandibular arch (AA 1) and the hyoid arch (AA 2). AA 3–6 remain associated with gills and are therefore sites of gas exchange (Figure 15.11). The lungfishes (Dipnoi) are an interesting comparison to the teleosts, as they provide insight into the closeness of the relationship between the arches and the respiratory system. As a group, lungfishes can use both gills and lungs for gas exchange (the efficiency and use of each are for a different chapter). They are equipped with gill filaments in the Australian lungfish, but only the two posterior pairs (and to a limited extent the most anterior pair) retain the capacity for gas exchange in African and South American species. This is functionally important because this design prevents oxygen loss to the hypoxic water when oxygen-rich blood from the lungs traverses the gills. AA 2, 5, and 6 interact with the gills for the purposes of gas exchange. AA 1 degrades during development, and AA 3 and 4 move blood directly to the dorsal aorta without engaging with the gills. These are lungfishes, so how do the lungs get their blood supply? A branch of AA 6, which we will call a pulmonary artery, directs blood to the lungs (Figure 15.12). The blood will then return directly to the heart instead of to the dorsal aorta. The blood will return to the heart via the pulmonary vein. A small shunt vessel, the ductus arteriosus, controls whether blood from these branchial arteries enters the dorsal aorta (systemic circulation) or pulmonary circulation. This configuration resembles that of embryonic tetrapods, where the pulmonary arteries develop from the sixth pharyngeal arch. In lungfishes, the oxygen-rich blood from the lungs bypasses the respiratory circulation by traversing the anterior gill arches and entering the systemic circulation. At this point, we have set the stage for further exploration of two significant themes: the loss/degradation of aortic arches during development and the evolution of the pulmonary circuit.

In bony fishes the gastrointestinal circulation has also received considerable study, as it is central not only to digestion but to other physiological processes such as ion/water regulation and acid-base homeostasis. In many cartilaginous fish, in common with other vertebrates, the gastrointestinal circulation is made up of three major vessels (i.e., celiac, mesenteric, and lienogastric arteries) that branch from the dorsal aorta. However, lamnid sharks (including mako sharks and great white sharks) show an unusual vascular arrangement associated with “regional endothermy”—that is, their capacity to maintain metabolic heat generated in swimming muscles. In lamnid sharks, the gastrointestinal arteries emanate from the third and fourth efferent branchial arteries and proceed to branch into a network (rete mirabile) that forms a countercurrent heat exchanger with blood returning from swimming muscles, allowing blood destined for the gastrointestinal tract to be warmed to aid digestion. Ray-finned fishes exhibit an unusual (among vertebrates) circulatory anatomy in that the major gastrointestinal arteries branch from the dorsal aorta in a common “coelomesenteric” artery before branching to supply different organs.

The invasion of land by the ancestors of the tetrapods represents a pivotal moment in transitioning from gills as the major organ of respiration to using the lungs. The modern amphibians are a useful illustration of how this transition occurred. The earliest diverging lineage, the salamanders, has some variability depending on the environment they live in (Figure 15.11). The fully aquatic salamanders (e.g., the mudpuppy Necturus) retain four aortic arches, similar to the fishes. Terrestrial salamanders have transitioned to three arches, having lost AA 1, 2, and 5. Critically, the pulmonary artery in terrestrial salamanders is now the direct branch of AA 6 from the ventral aorta (and AA 6 is now just referred to as the pulmonary artery). There is the ductus arteriosus that connects the pulmonary artery to the dorsal aorta, but it is much smaller than the pulmonary artery. The small vessel is also critically important in human development, which we will discuss toward the end of this chapter. The frogs and toads (Anurans) have taken the transitions even further. AA 3 and 4 have lost their connection to each, effectively severing AA 3’s role in supplying blood to the dorsal aorta. The ductus arteriosus is also lost; blood from AA 6 is now completely directed to the lungs. At this stage, the pulmonary circuit is completely separated from the systemic circuit. The nonavian reptiles will show a very similar setup to that of the anurans. In some groups (snakes), small ducts will remain to connect AA 3 and 4. There are two important distinctions that we need to make note of now. The first is that AA 4 is now simply referred to as the aortic arch. This will continue to be the case in birds and mammals. The second is that the blood supply for the aortic arch is divided in the reptiles. Changes in the structure of the heart (discussed below) will change which “type” of blood enters the right and left aspects of the aortic arch. For the right aortic arch, it will receive only blood that has been oxygenated. The left aortic arch will receive a mix of oxygenated and deoxygenated blood.

As we conclude our journey with the birds and mammals, there are only a few (but important!) changes that are going to occur. The truncus arteriosus is what will eventually be named the ventral aorta in many vertebrates or simply the aorta in humans. AA 3 will be unchanged, and it will be referred to only by the names of its major branches: external carotid, internal carotid, and subclavian (birds only). The aortic arch (AA 4) will lose one of its major vessels, no longer being a paired vessel. In birds, the right side of the aortic arch is retained and is no longer always referred to as the dorsal aorta, instead simply being referred to as the aorta or descending aorta. The mammals will retain the left side of the aortic arch but keep the names “aorta” and “descending aorta.” The abdominal aorta will also sometimes be used, particularly in humans. The right side of the aortic arch is partially retained in humans, becoming the subclavian artery that we identified as belonging to AA 3 in birds. It is important to note that the subclavian artery in birds is not homologous to that of mammals, as they have different developmental origins despite their shared probable function (bringing oxygenated blood to the forelimb).

Hearts

Let’s take a look at the nonvertebrate chordates first. The circulation of cephalochordates relies on multiple contractile vessels and a single heart that can be difficult to find on specimens. For a long time, that difficulty spurred the widespread belief that they lack a heart, but a ventral linear heart tube that is homologous to the heart of vertebrates can be defined by molecular markers and developmental genetics. The cephalochordate heart is fairly simple—it is composed of a valveless and uncompartmentalized contractile tube made up of a single layer of nonstriated muscle, which resembles the linear heart tube during the early developmental stage of vertebrates (see Figure 15.13).

The heart in urochordates is much easier to find. Like the heart of cephalochordates, the single-chambered tunicate heart lacks valves. The heart is enclosed within a rigid pericardium, and experimental puncturing of the pericardium greatly disturbs cardiac function, indicating that it is important for the heart to work properly. Both cephalochordates and tunicates lack nervous innervation of the heart.

Cyclostomes

Cyclostome hearts are three chambered. Chambers are separated by leaflet-shaped valves, which provide for a unidirectional circulation. Poorly oxygenated blood enters the sinus venosus, followed by the atrium, and the more muscular ventricle (Figure 15.7). The heart is encased in a pericardial sac. These hearts are homologous to other vertebrate hearts; however, like cephalochordates and tunicates (and unlike most other vertebrates), the hearts of cyclostomes are devoid of a coronary circulation to provide blood to the heart muscle itself. The lamprey heart is innervated by the vagus nerve, but innervation differs from the jawed vertebrates by being excitatory—that is, it increases heart rate. The hagfish heart lacks cardiac innervation altogether.

Hagfishes have several accessory “hearts,” which are not homologous with other vertebrate hearts; their job is to return blood toward the heart. The caudal heart is located posteriorly and moves blood from the sinuses near the caudal trunk and kidneys back to the main (systemic or branchial) heart. The abdominal portal heart is responsible for pumping blood from the intestines to the liver; it is an enlarged portion of the hepatic portal vein. The cardinal hearts in the anterior part of the body move blood from sinuses in the head back to the systemic heart via the inferior jugular vein. All the accessory hearts are capable of contraction and give an extra boost to the venous blood pressure to get blood back to the heart. Interestingly, the hagfish accessory hearts, except for the caudal heart, do not appear to be under the control of nerve signals. Lampreys have no accessory hearts, instead relying on a fairly large systemic heart.

Chondrichthyes and Actinopterygii

The other fish hearts are four chambered (but not in the same configuration as the human heart). Blood passes through, in series, the sinus venosus, atrium, ventricle and outflow tract. The compositional nature of the outflow tract varies and is broadly defined as a muscular conus arteriosus in Chondrichthyes and nonteleost Actinopterygii or, in teleosts, a bulbus arteriosus mainly composed of elastin and smooth muscle. While the bulbus arteriosus is the most obvious structure of the teleost outflow tract, a small conus arteriosus persists between the ventricle and the bulbus arteriosus (Figure 15.13).

Cartilaginous and ray-finned fish often exhibit complex and variable ventricular architecture. The ventricular wall can be divided into an outer “compact” layer and an inner trabeculated “spongy” layer of cardiac muscle (myocardium). Cartilaginous and at least some ray-finned fishes both have coronary arteries to bring blood to the cardiac muscle itself, but the layers they serve differ between fish groups. In cartilaginous fishes, the coronary arteries are widespread and nourish both the compact layer and spongy myocardium. In ray-finned fishes, the coronary arteries are confined to the compact layer, and the spongy layer relies on oxygen supply from the oxygen-poor venous blood that returns to the heart. However, teleosts have lost the compact myocardium and exhibit an avascular heart composed of only spongy myocardium. Surprisingly, this does not necessarily limit cardiac performance; some teleosts with spongy hearts exhibit comparable capacity to those with compact hearts. However, the most athletic teleosts, such as tuna, exhibit greater proportions of compact myocardium.

Nervous innervation of the heart is well developed in these groups of fishes. Ray-finned fishes, like other jawed vertebrates, exhibit a characteristic double innervation of the heart from the autonomic nervous system composed of inhibitory parasympathetic innervation from the vagus nerve and excitatory sympathetic innervation (Chapter 19—Peripheral Nervous System). Cartilaginous fishes lack sympathetic innervation, although it is unclear if this represents an ancestral state or secondary loss.

Box 15.2—Plumbing for Air-Breathing Organs

As mentioned in Chapter 14, the ability to breathe air through specialized gas-exchange organs (air-breathing organ, ABO) has evolved many times in osteichthyes, and the ABO must be accommodated into the circulation. While the vascular anatomical arrangement varies depending on the precise nature of the ABO (which may be represented as simple modification of the buccal cavity to specialization of the swim bladder or even co-option of the gastrointestinal organs), blood always returns to the veins en route to the heart and thus the gills before it reaches the systemic tissues (Figure 15.14).

Indeed, it has been suggested that air breathing may have evolved in fishes primarily for cardiac oxygenation during exercise. Remember that the coronary arteries only reach the spongy layers of most actinopterygian hearts. It is possible that adding some oxygenated blood prior to reaching the heart helps deliver some oxygen to the heart. However, high vascular resistance means the ABO could not be placed elsewhere in circulation. A more likely possibility may have to do with hypoxic (low-oxygen) environments, another situation where having some extra oxygen in the bloodstream might be helpful.

Actinopterygians with no ABO simply increase their gill ventilation rate in hypoxic conditions, which allows them to uptake more oxygen, even if it may not be enough. For fishes with an ABO, it has long been believed that when fish breathe air in hypoxic water, they risk losing oxygen as blood traverses the gills (down an oxygen concentration gradient). However, recent studies indicate that little oxygen is lost in hypoxic conditions, even though carbon dioxide excretion is still maintained at the gills. How does this work? ABO-bearing fishes decrease their gill ventilation rate in hypoxic waters, which makes the ABO the primary site of gas exchange, not the gills.

Remarkably, at least in one teleost species, the northern snakehead Channa argus, it has been shown their undivided ventricle can maintain separate streams of blood flow and keep the poorly oxygenated blood from the systemic tissues separated from the more oxygenated blood from the ABO. This is likely a consequence of having not one but two aortas. Well-oxygenated blood returning from the gills is primarily directed to the systemic circulation via the posterior gill arches, which have poorly developed gill filaments that therefore won’t lose much oxygen. Oxygen-poor blood enters the anterior gill arches before reaching the ABO for aquatic and aerial gas exchange, respectively.

Sarcopterygii

As implied by the name, lungfishes (Dipnoi) are characterized by well-developed lungs. These are homologous to those of tetrapods (see Chapter 14—Respiratory System). As we mentioned above, the shift to breathing with lungs resulted in a lot of replumbing of the circulatory system. This includes the heart (Figure 15.15). Lungfishes give us a good glimpse into how the heart adapted to this new circulatory pattern. The atrium is partially divided by a small sheet of connective tissue called the pulmonalis fold. Oxygen-rich blood returns from the lungs in a distinct pulmonary vein, which passes over the sinus venosus dorsally. From here, the blood enters the atrium to the left of the pulmonalis fold and therefore into the left part of the atrium. The oxygen-poor blood from the systemic circulation enters the right side of the atrium.

The ventricle is partially divided by a septum to keep these two streams of blood separated. The septum does not reach the orifice of the conus arteriosus. In South American and African lungfish, the conus arteriosus maintains separate streams of blood flow by virtue of a spiral fold of connective tissue. There is no spiral fold in the Australian lungfish, but this species has numerous valves in the conus arteriosus. Lungfishes have the most unusual atrioventricular valve (the valve between the atrium and ventricle), as it is basically a ball of connective tissue rather than leaflets. Closure of the atrioventricular canal is achieved by the myocardium contracting against the “ball.”

The lobe-finned fishes also include the coelacanths. Their hearts resemble those of other actinopterygii nonteleost fish, but the chambers are somewhat stretched out on the caudo-cranial axis. The most pronounced deviations are the presence of trabeculations in the sinus venosus and the presence of a pulmonary vein that opens into the sinus venosus but is filled with fat and thus nonfunctional with regard to blood flow. The atrium, ventricle (with well-developed coronary arteries), and outflow tract are all undivided. Given the famously elusive nature of these fish, there has unfortunately been little opportunity for detailed molecular and physiological studies of their cardiovascular system.

Tetrapods

Amphibians and nonavian reptiles retain a sinus venosus, like other ectothermic vertebrates (i.e., the fishes), which receives the systemic venous blood prior to the right atrium. The sinus venosus contracts prior to the atrium and contributes to the filling of the atrium. Interestingly, in both mammals and birds, the myocardium of the sinus venosus retains its function, but its contraction now occurs simultaneously with that of the atria. In this way, the sinus venosus has been lost as a separate chamber in these groups. The functional significance let alone importance of this evolutionary convergent evolution is elusive. In terms of the cardiac outflow tract, amphibians retain a conus arteriosus, while in amniotes (reptiles and mammals) it is largely assimilated into the ventricle, or “ventricularized” (in Figure 15.13, notice how the structure labeled “C”—for conus—is gone in reptiles and mammals). Experimentally, this process has been shown by labeling the outflow tract of young chicken embryos, and days later the labeled tissue is within the right ventricle.

For the vast majority of amphibians, the atrium is completely divided, with the left atrium receiving pulmonary blood and the right atrium receiving systemic blood (Figures 15.13 and 15.17). We see an exception to having completely divided atria in salamanders who lack lungs as adults, such as those in the family Plethodontidae. Without lungs, there is no need for a pulmonary artery. Thus, these salamanders have either a missing atrial septum or an incomplete one. Tiny frogs sometimes also lack or have an incomplete atrial septum.

The amniotes have complex hearts that achieve separation of oxygen-rich and oxygen-poor blood in several different ways. The atria are completely separated into left and right atria (Figure 15.13). As we saw in amphibians, the left atrium receives pulmonary blood, and the right atrium receives systemic blood. Much of the variation across amniotes instead has to do with ventricle structure.

Unlike the lungfishes, many amphibian hearts have an undivided ventricle (Figures 15.16 and 15.17). Yet the oxygen-rich and oxygen-poor blood are kept largely separate by well-developed trabeculae. While the heart is filling with blood during diastole, it pools in the large pockets created by the trabeculae. Blood entering the ventricle from the left atrium tends to stay in the left trabecular pockets, and blood from the right atrium tends to stay on the right. When the heart contracts during systole, blood stays separated as it moves into the conus arteriosus. However, some salamanders, like the hellbender Cryptobranchus alleganiensis, have ventricles with a partial septum to assist. Regardless of whether there is a septum in the ventricle or not, the conus arteriosus contains a spiral valve, similar to some species of lungfish, which keeps the blood from each side of the ventricle separated.

In most nonarchosaur reptiles, the ventricle is not fully divided by a septum, although oxygen-rich and oxygen-poor blood deriving from the left and right atria, respectively, are kept well separated (Figure 15.16). This is aided by discrete subchambers; the cavum venosum, the cavum pulmonale and the cavum arteriosum (Figure 15.18). Oxygen-poor blood from the right atrium is received in the cavum venosum and overflows into the cavum pulmonale, from where it is mainly ejected into the pulmonary circulation during systole. When the well-oxygenated blood returns to the left atrium via pulmonary veins, blood passes into the cavum arteriosum from where it is ejected into the systemic circulation (left and right aortic arches) after crossing the cavum venosum during ventricular contraction. Because oxygen-poor blood and, later in the cardiac cycle, oxygen-rich blood both pass through the cavum venosum, it is a site of limited mixing of blood.

Many reptiles (as well as some amphibians and fishes) have the ability to change their circulatory patterns. These cardiac shunts (Figure 15.19) occur when changes in systemic or pulmonary artery resistance make passage into one circulation less favorable, and so blood is diverted for a short period of time. For example, pulmonary artery vasoconstriction, stimulated by the vagus nerve, increases pulmonary resistance and diverts a greater proportion of oxygen-poor blood toward the systemic circulation. This situation is typical of resting states or during diving in aquatic species such as sea turtles. This action is known as a right-to-left or pulmonary bypass shunt. The “right-to-left” indicates that systemic oxygen-poor blood from the right atrium is moving directly back to the systemic circulation (associated with the left side of the ventricle)—it’s bypassing the pulmonary circuit. Left-to-right or systemic bypass shunts may also occur where well-oxygenated blood is shunted from the left atrium back to the respiratory organs, bypassing the systemic circulation. For example, the freshwater red-eared slider turtle Trachemys scripta uses a left-to-right shunt when it returns to the surface after diving.

The archosaurs (including birds) and mammals share a generally similar plan. Both the atria and the ventricles are completely divided into left and right (Figures 15.13 and 15.16). Oxygen-rich blood from the pulmonary circulation is received by the left atrium and then moves into the left ventricle and out to the systemic circulation (Figure 15.9). Oxygen-poor blood is returned to the heart from the systemic circulation and into the right atrium, followed by the right ventricle, and then exits to move to the pulmonary circulation. In all three groups, the left ventricle is larger and more muscular, reflecting the need to generate higher blood pressure to move the blood throughout the entire body.

Crocodylians, unlike the other archosaurs, have a complete ventricular septum dividing the right and left ventricles (Figure 15.16). It very much resembles that of mammals by being almost exclusively myocardial except for a small membranous septum immediately below the base of the arteries. In birds, the configuration is the same, but the connective tissue of the membranous septum differentiates to myocardium in late development.

Crocodylians, like other nonavian reptiles, retain two aortic arches, wherein the right aortic arch exits the left ventricle, and the left aortic arch exits the right ventricle along with the pulmonary artery (Figure 15.20). The left and right aortae communicate via an opening, the foramen of Panizza, in their shared vessel wall, close to the ventricular outflow valves. This anatomical arrangement means that, in common with other nonavian reptiles, crocodylians are capable of central shunts despite the ventricular septum. The left aorta can receive oxygen-rich blood from the left ventricle via the right aortic arch and the foramen of Panizza, or when pulmonary vascular resistance is high, oxygen-poor blood from the right ventricle is ejected into the left aorta (a right-to-left shunt as described above, Figure 15.19). This mechanism is partially supported by the “cog-teeth valve” at the base of the pulmonary artery, which gates blood flow to the lungs. Like other reptiles, the ensuing right-to-left shunt is typical of resting submergence. Crocodylians are incapable, however, of left-to-right shunting. Mammals and birds cannot shunt at all.

Endothermy and the Amniote Heart

Remember that archosaurs and mammals represent two different evolutionary lineages and that the general anatomy of these hearts represents convergent features. If we leave nonavian archosaurs aside, we can see a possible reason for the convergence: endothermy. Endothermy (the capacity to maintain a high stable body core temperature) likely evolved at least twice in amniotes: in mammals and in birds (although there is evidence of endothermy within the nonavian dinosaurs as well). The higher metabolic demands of endothermy are associated with cardiovascular changes including faster heart rates, higher systemic blood pressures, and lower pulmonary blood pressures. Both birds and mammals are characterized by complete ventricular division and both only have one aortic arch with no shunting. The completely separated pulmonary circulation allowed the evolution of lower blood pressures and a thinner blood-gas barrier (see Chapter 14 on the respiratory system). There is also a clear transition between the mixture of compact and spongy myocardium seen in ectotherms. Hearts of ectotherms are often dominated by a spongy trabeculated wall with extensive lumens and only a thin compact layer, whereas endotherms tend to have a highly compact wall, which may have only a few large lumens (Figures 15.16 and 15.21, Box 15.3). Presumably, this is an important adaptation to facilitate faster ventricular filling required for the higher heart rates of endotherms. The thick compact wall requires an extensive coronary artery supply, whereas ectotherms derive much of their cardiac oxygenation from venous luminal blood. While forms of coronary arteries are found across jawed vertebrates, they have likely evolved independently in different lineages, although the coronary arteries of amniotes are likely homologous.

Another potential convergent link to endothermy has to do with the processes involved in the initiation of cardiac contraction. Recall from Chapter 11 that muscles contract when an action potential is reached. The hearts of most mammals and birds have a cardiac conduction system that starts each heartbeat and the electrical activation of the chambers, but hearts of ectotherms are generally without this system. The cardiac conduction system is composed of heart muscle cells with specializations for impulse generation (pacemaking), fast electrical propagation, or both. Most upstream is the sinus node (SA node), the dominant pacemaker of the heart (Figure 15.22). If present, it sits in remnants of the embryonic sinoatrial junction. A somewhat similar structure sits in the remnants of the embryonic atrioventricular junction; this is the atrioventricular node (AV node). This node can also spontaneously generate action potentials, but this normally occurs at a slower rate than the SA node. The primary function of the AV node is to delay electrical propagation because it gives the time it takes for atrial contraction to finish the filling of the ventricles.

From the AV node extends the bundle of His (named after a Swiss anatomist and also called the AV bundle), which is the fast and only electrical connection between the atrial and ventricular myocardium. It reaches the crest of the ventricular septum, then drapes over the ventricular septal surfaces as the left and right bundle branches. From there it terminates into the peripheral conduction system of Purkinje cells (also called Purkinje fibers). In mammals, the peripheral conduction system is mostly restricted to the ventricles, while it can occur in a less developed state in the atria. By contrast, in birds the peripheral conduction system is very extensive in both the atria and the ventricles, and for reasons that are poorly understood, the sinus and atrioventricular nodes can be quite inconspicuous and in this sense underdeveloped relative to mammals.

We just finished examining the evolution of the blood circulatory system in terms of tracking changes across various vertebrates. There is a lot to keep track of! We have provided a visual summary in Figure 15.23.

Lymphatics

Remember that we have a second circulatory system to follow—the lymphatic system. Unfortunately, the evolutionary story of the lymphatic system is murky. While scientists have a good understanding of the tetrapod lymphatic system, that of the fishes is still up for debate thanks to the presence of the secondary vascular system (SVS) in many extant fishes (Figure 15.24). The SVS is composed of vessels that contain blood, but do not receive it directly from the heart. Instead, there are special connections called interarterial anastomoses that are so large that even erythrocytes can enter the SVS, at least under some circumstances. Importantly, these SVS vessels serve the external-most parts of the fish body, the fins and body surfaces, and run in parallel to the primary blood circulation. While this means that the fluid in the SVS is not filtered fluid as the lymph of tetrapods is, the structure of the SVS capillaries is very similar to tetrapod lymphatic capillaries. Moreover, both systems operate under low-pressure regimes. Perhaps the SVS could be considered a lymphatic system precursor. Studies on zebrafish (a teleost and model organism) over the last two decades have suggested that zebrafish potentially have a proper lymphatic system. This makes sense if you recall that the lymphatic system has an important role to play in immune function—that’s a good function to have! However, two recent studies on zebrafish have suggested that some aspects of the SVS transition into lymphatic vessels, meaning that zebrafish may have some sort of hybrid SVS-lymphatic system. For now, we can say that ray-finned fishes have some sort of lymphatic system that is somewhat similar to mammals, but it remains to be determined how the SVS fits into the evolutionary story, and much may be learned from reexamining cyclostomes or chondrichthyans.

If we look at our closest extant fish lineage to tetrapods, the lungfish, we see the lack of the SVS, and the lymphatic system looks more similar to that of mammals than that of the zebrafish. There is no input directly from the blood into the lymphatic capillaries (just interstitial fluid), and the structure of the lymphatic capillaries is similar to mammals. However, lungfish lymphatic capillaries do not merge into lymphatic vessels. Instead, lymph is immediately pumped into the adjacent blood capillaries by micropumps, tiny lymphatic hearts that are unique to the Dipnoi.

Once we get to the tetrapods, the lymphatic system follows the same general plan described in Section 15.2. Pressure in the lymphatic system is generated by adjacent skeletal muscle and, when present, lymphatic hearts. As we see in blood vessels, lymphatic hearts have three layers: an endothelial tunica interna, a muscular tunica media, and a tunica exterior composed of connective tissue. The number of lymphatic hearts varies widely across tetrapods and within tetrapod groups (Figure 15.25). Within the amphibians, caecilians can have up to 200 lymphatic heart pairs, whereas different salamander species have anywhere from 8 to 23 pairs. Lymphatic hearts are also found in all extant reptiles (including Aves). As with the amphibians, their location and number vary. Mammals are the only tetrapods that do not have lymphatic hearts.

Anurans (frogs and toads) only have two pairs of lymphatic hearts. However, like just about every other part of their body, anuran lymphatic systems are highly specialized. Anurans have a series of subcutaneous lymph sacs that are connected via muscularly controlled unidirectional valves (Figure 15.25). The lymph sacs themselves are not contractile. Compression of the sacs forces lymph toward the lymphatic hearts, which in turn provides that extra boost of pressure to get the lymph returned back to the veins. Compression happens in two ways, through contraction of surrounding skeletal muscles and through increased pressure from the lungs as they inflate during breathing. Exhaling is also useful for the movement of lymph in frogs—as the lungs deflate and volume decreases, the subvertebral sinus expands due to sharing a pleural membrane with the lungs. The increase in subvertebral sinus volume creates a drop in pressure, which draws lymph into the lymphatic sacs. When the frog inhales again, that new lymph is moved toward the lymphatic hearts.

15.5 Human Circulatory System

The human heart has four chambers, a solitary pulmonary trunk, and an aorta, as does any mammal (Figure 15.26). But there is substantial variation between mammals in the number of veins that connect to the atria, the configuration of the right atrioventricular valve, and more. Perhaps the human vasculature also has unique features—for example, as an adaptation to bipedalism—but such features may be subtle, and their impact could be widely distributed in the vast circulatory network. Either way, what is unique about the human circulatory system is most readily seen and investigated at the level of the heart.

In humans and eutherian mammals generally, the gestational formation of the atrial septum is particularly complicated. It involves the formation of a primary septum that is later perforated such that a large foramen ovale forms. The foramen ovale enables blood to cross to the left atrium and bypass the pulmonary circulation of the developing embryo that does not use the lungs for gas exchange. The foramen is closed after birth because the perforated atrial septum butts against a part of the atrial roof that folds into the right atrial cavity. The remnant of this process is the circular depression, the oval fossa, on the right atrial side of the atrial septum. Approximately one out of four humans will have an imperfectly closed atrial septum, or so-called patent foramen ovale. Because the pressure in the left atrium is higher than in the right atrium, the patent foramen ovale is effectively closed in most circumstances. In humans and eutherian mammals generally, the right atrioventricular valve comprises leaflets coming off from the right ventricular free wall and the ventricular septum. In contrast, in monotreme and marsupial mammals, the right atrioventricular valve is dominated by a large leaflet coming off the free wall.

A variable feature of mammal hearts is the number of systemic veins that connect to the right atrium, which is typically three but only two in primates (these veins are the so-called caval veins). The number of pulmonary veins connecting to the left atrium is particularly variable; it may vary between one and seven depending on the species, and it is typically four in primates. In humans, these veins undergo remodeling only in the fetal period, whereas the vast majority of morphogenetic processes have already taken place in the embryonic period. Only in the second trimester will the left superior caval vein begin to regress, or about two months after it has initially formed. A remnant of it always persists as the coronary sinus into which the coronary circulation drains. The regression leaves the (right) superior caval vein as the sole conduit for the systemic venous blood returning from the upper limbs and the cranial circulation. The regression proceeds to a different extent between individuals, and a few can be born with a persistent left superior caval vein. Around the same time the left superior caval vein regresses, the pulmonary venous tree will be incorporated into the posterior wall of the left atrium up to around the second branching point. In this way, over the course of a month, one pulmonary venous orifice becomes two and then four (and five in about 20% of us).

Growing evidence suggests that the primate left ventricle is relatively rich in trabeculation and that the human left ventricle, while still quite trabeculated, may be less trabeculated than in great apes. The functional implications of the degree of trabeculation in the left ventricle are not clear, but a lower degree of trabeculation appears to set the human heart apart from that of our closest relatives.

15.6 Circulatory System Integration

The circulatory system is tightly integrated with several other systems. The reproductive system, endocrine, digestive, and more all rely on the circulatory system to transport their products across a body. However, as you may have gathered from this chapter, the evolution of the circulatory system is most tightly correlated with the respiratory system. As the respiratory system has changed over evolutionary time (see Chapter 14—Respiratory System), the circulatory system has changed alongside it. Blood vessels have vanished, and new ones have evolved to adjust to the changes in primary mode of respiration. The changes to the aortic arches very closely mirror the changes to the respiratory system. The size and complexity of the heart have also adjusted across the history of vertebrates. Chambers have been added and others subsumed. Changes to metabolic rate and the nervous system have altered the heart’s structure.

15.7 Summary

The circulatory system works to move blood around the body and in doing so transport oxygen and nutrients to the tissues that need them. The circulatory system must continue to function as long as the individual is to remain alive. The physics of fluid flow is paramount to linking the structure of the circulatory system to the function. The heart is muscular with multiple chambers, directing blood flow to large vessels that carry the blood to where it is needed. Thick-walled arteries will resist intense pressures as blood leaves the heart. Capillaries are extremely small and thin walled to allow for the diffusion of oxygen, carbon dioxide, and nutrients across tissues. The circulatory system is most tightly connected to the respiratory system, their shared responsibility of gas exchange greatly influencing the evolution of both systems. Beginning with a basic pump and series of tubes, the many vertebrate groups have tinkered with and tweaked these structures to optimize the delivery of blood. In examining these tweaks and changes, there is real insight into the evolutionary history and ecology of these vertebrates.

15.8 Further Reading

1. Burggren, W.; Farrell, A. P.; Lillywhite, H. B. “Vertebrate cardiovascular systems.” In Handbook of Physiology; Wiley: Hoboken, NJ, USA, 1998; pp. 215–308.
2. Poelmann, Robert E., and Adriana C. Gittenberger-de Groot. “Development and evolution of the metazoan heart.” Developmental Dynamics 248, no. 8 (2019): 634–656.

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