4 The Cardiovascular System

The cardiorespiratory system of fishes, as for other vertebrates, is designed to efficiently transport a plethora of substances and molecules, including respiratory gases, hormones, metabolites, electrolytes, nutrients, plasma proteins, immune factors, signaling molecules, and wastes, among the tissues. The fish cardiovascular system is composed of four fundamental components: blood; heart(s); vasculature; and a control system. This chapter broadly describes the general features of the fish cardiovascular system, highlighting the latest ideas, advances, and research in the field, and details some of the integrated responses of this system to changes in ambient and internal conditions.

4.2 General Features of the Fish Cardiovascular System

4.2.1 Blood

Blood serves to transport substances throughout the body (Fänge 1992; McDonald and Milligan 1992; Olson 1992). It is composed of red blood cells (RBCs, erythrocytes), white blood cells (WBCs, leukocytes), and plasma (extracellular fluid that contains proteins, ions, hormones, nutrients, metabolites, and wastes). The total blood volume is in the range of 3–4% of body mass in most teleost fishes and 5–8% of body mass in most elasmobranchs (Olson 1992). Antarctic icefishes (Nototheninoid fishes from the family Channichthyidae) do not have RBCs, and their blood volume is approximately four times higher than that of typical fishes (Wells 2005). Hagfishes top all known fishes, with a blood volume of ~18% of body mass (Farrell 2007b).

RBCs serve to transport oxygen and carbon dioxide and regulate acid–base balance (Nikinmaa 1990; Fänge 1992). In contrast to mammals, fish RBCs are nucleated and thus, can synthesize proteins in the circulation. Fish blood is red (except in icefishes) because their RBCs contain hemoglobin. The hemoglobins of fishes are tetrameric (built of four polypeptide chains), with the exception of hagfishes and lampreys, which have monomeric and dimeric hemoglobins. Hematocrit (% of blood volume that is occupied by RBCs) varies widely across fishes, from 0% to >50%, though in most teleosts, it tends to range from 20% to 40%. Blood viscosity increases with hematocrit and cold temperatures, which results in high vascular resistance and high cardiac workload. Accordingly, fishes in cold, stable environments often have a lower hematocrit, which serves to decrease blood viscosity (Wells 2005).

The primary role of WBCs is in immunity and cellular defense (Fänge 1992). Leucocrit (% of blood volume that is occupied by WBCs) constitutes a tiny proportion of blood volume (0.3–1.0%). There are four major types of WBCs: lymphocytes, thrombocytes, granulocytes, and monocytes (Fänge 1992). Lymphocytes are common and are involved in immuno-competence and antibody production. Thrombocytes are small and play a role in blood clotting. The function of granulocytes is unknown, but they are thought to play a diversity of roles, including in the inflammatory response, blood coagulation, tissue repair, and phagocytizing microorganisms. The largest and rarest WBCs are the monocytes, which are phagocytic (ingesting harmful cells, particles, and bacteria). Infection and parasitic infestation typically result in an increase in circulating WBC levels, while stress and environmental toxicants can modulate levels and thus influence disease resistance.

The components of the blood are tightly regulated; thus, blood sampling is a common technique to assess the physiological status of a fish. Numerous hormones are transported in the plasma (e.g., gonadotropins and sex steroids, growth hormone, thyroid hormones, and cortisol). Metabolite levels can be highly variable in the plasma. Lactate, the end product of anaerobic metabolism, accumulates in the blood following strenuous activity (e.g., exhaustive exercise) and in response to oxygen limitation (hypoxia: decreased oxygen; anoxia: no oxygen). Anoxia-tolerant fishes such as crucian carp (Carassius carassius), and its close relative the goldfish (Carassius auratus), produce ethanol in response to severe hypoxia or anoxia (Fagernes et al. 2017). The major plasma electrolytes in fishes are Na⁺ and Cl⁻, whereas plasma Mg²⁺, K⁺, and Ca²⁺ are found at much lower levels. Amino acids are transported within the RBCs and in the plasma, while lipoproteins transport lipids in the plasma. Several plasma proteins are present in the blood (including albumin, Ca²⁺-binding proteins, and immunoglobulins). In addition, some teleosts in polar regions can produce antifreeze proteins or antifreeze glycoproteins to inhibit ice crystallization within body fluids that would otherwise be fatal (DeVries and Cheng 2005).

4.2.2 Heart Morphology and Blood Flow Patterns

The fish heart is composed of morphologically distinct regions (segments). Classically, the fish heart was considered to be composed of four chambers arranged in series: the sinus venosus, atrium, ventricle, and bulbus (in teleosts; or conus in elasmobranchs) arteriosus. However, the current consensus is that the fish heart consists of six components (or segments) arranged in series within the pericardium. These are the sinus venosus, atrium, atrioventricular (AV) segment, ventricle, conus arteriosus, and bulbus arteriosus, the latter two of which are collectively termed the outflow tract (OFT) (Icardo 2017) (Figure 4.1). The Cyclostomata (hagfish and lampreys) present an exception. In these species, all components of the OFT are absent (Farrell 2007b).

FIGURE 4.1 Anatomical organization of the teleost heart. Direction of blood flow is from right to left.

The thin-walled sinus venosus serves as a reservoir that receives venous blood from the ducts of Cuvier and hepatic veins and subsequently conveys it to the atrium through the sino-atrial (SA) valve (Icardo 2017) (Figure 4.1). The wall of the single atrium is formed by myocardial trabeculae that generally converge to the AV orifice, thereby enabling blood to be expelled to the single ventricle through the AV valves of the AV segment. Ventricular contraction is responsible for generating the heart’s output and central arterial blood pressure. As such, the ventricle wall is comprised almost entirely of myocardial cells. Generally, but not exclusively, relative ventricular mass (i.e., ventricular mass/body mass × 100) is positively correlated with higher blood pressure generation and athletic performance and ranges from ~0.03% to ~0.3%–0.4% across species (Farrell and Jones 1992).

Ventricular myocardial architecture is highly variable among species. Inter-specific variation is classified into two broad categories: fish having a completely trabeculated ventricle (termed spongiosa or spongy myocardium) and those having a ventricle with an outer compact layer in addition to an inner spongy layer. Spongy myocardium is typically avascular (but see later), so oxygen and nutrients are supplied to the spongy myocardium via the venous blood being pumped through the lumen of the ventricle. As such, the spongy myocardium is the last tissue to receive oxygen before the blood is re-oxygenated at the gills. In contrast, compact myocardium has a coronary circulation (see Section 4.2.4), so it receives a reliable source of oxygen. Historically, a completely spongy ventricular myocardium was thought to be associated with sluggish fish with a low cardiac performance, whereas the presence of a compact layer was believed to be associated with very active fishes, such as salmonids (Icardo 2017). However, this distinction has been blurred by studies showing that some fish with an entirely trabeculated ventricle (e.g., the gilthead seabream; Sparus auratus) are able to maintain high heart rates and cardiac output similar to those recorded in highly athletic fish (Icardo 2017). Fish ventricles are further divided into four morphological categories (Types I–IV) according to the presence of compact myocardium and cardiac vascularity (Farrell and Smith 2017; Icardo 2017). Type I ventricles, which are found in all cyclostomes and approximately 50% of adult teleost species, are completely composed of spongy myocardium and lack a coronary circulation. Type II ventricles are composed of spongy and compact components, but a coronary circulation is only associated with the compact myocardium (e.g. salmonids). Type III and Type IV ventricles are characterized by vascularization of both the compact and spongy myocardium (e.g. sturgeon, elasmobranchs, some tuna), and the original distinguishing morphological feature between the groupings was the proportion of compact myocardium. However, due to the realization that inter-specific phenotypic plasticity exists for the proportion of compact myocardium, that the function of the compact myocardium is consistent regardless of its proportion, and that the various methodologies utilized to quantify the proportion of compact myocardium can return different results, it has been suggested that the Type III and Type IV division is unnecessary (Farrell and Smith 2017; Icardo 2017).

Ventricle contraction propels blood through the OFT, which contains components of both the conus arteriosus and the bulbus arteriosus in different proportions depending on taxa (Icardo 2017). In basal species such as rays, sturgeons, and bichirs, the conus arteriosus constitutes the major component of the OFT, and the bulbus arteriosus is a short ring-like portion that establishes a structural connection to the ventral aorta. In contrast, in more advanced teleosts such as the European eel (Anguilla anguilla) and yellowfin tuna (Thunnus albacares), the bulbus arteriosus predominates in the OFT, whereas the conus arteriosus is a short muscular ring situated between the ventricle and the bulbus arteriosus (Figure 4.1). The bulbus arteriosus of advanced teleosts has a structure like that of an artery and contains collagen, elastin, and smooth muscle cells. The cellular composition of the bulbus arteriosus allows it to be highly compliant, thereby dampening the fluctuation in blood pressure that occurs with ventricular contraction (termed the Windkessel effect), sheltering the gill vasculature from high systolic blood pressure, and leading to a more uniform perfusion of the gill vasculature (Farrell and Smith 2017; Icardo 2017).

After transiting the OFT, blood flows through the ventral aorta and then on to the gills (branchial circulation), where gas and ion transfer occurs. Blood flow then continues via the dorsal aorta to the peripheral tissues (systemic circulation) before returning to the heart (Figure 4.2). Thus, in fishes, the branchial and systemic circulations are in series (i.e., single circuit circulation). In air-breathing fishes, the branchial and systemic circulations are still in series, but the circulatory system is modified to accommodate blood flow to and from the air-breathing organ (or lung, in the lungfishes) (Figure 4.2). Although considerable variation exists among air-breathing fishes in terms of the type and specific location of the air-breathing organ within the circulation, in most species, the air-breathing organ serves to increase the partial pressure of oxygen in the blood supplying the heart (Figure 4.2) when venous oxygen return to the heart might otherwise become limiting, including during exposure to aquatic hypoxia, swimming, digestion, and elevated temperature (Graham 1997; Stecyk 2017).

FIGURE 4.2 Generalized circulatory patterns found in (a) water-breathing fish, (b) air-breathing fish, and (c) lungfish. The lungfish circulation shows aspects of the double circulation (i.e., respiratory and systemic circulations in parallel) found in mammals. Deoxygenated blood leaves the right side of the heart and travels to the gills and lung to be oxygenated, whereas oxygenated blood exits the left side and flows to the tissues via modified gill arches. Morphological modifications of the heart serve to separate oxygenated and deoxygenated blood.

4.2.3 Cardiac Excitation–Contraction Coupling and Cardiovascular Parameters

The coordinated pumping action of the fish heart is initiated by action potentials (APs) generated by the pacemaker cells located in a morphologically distinct ring of tissue at the base of the sinoatrial valve (Vornanen 2017). The pacemaker cells set the spontaneous rhythm of cardiac contraction, and this results in a synchronized propagation of excitation throughout the atrium and ventricle. The generation of the AP, and its spread throughout the heart, requires the integrated activities of several sarcolemma (SL) ionic currents that pass through pore-forming ion channel proteins, namely voltage-gated Na⁺ channels (I_Na), L-type Ca²⁺ channels (I_CaL), T-type Ca²⁺ channels (I_CaT), delayed-rectifier K⁺ channels (including rapid [I_Kr] and slow [I_Ks] components), and background inward-rectifier K⁺ channels (I_K1) (Vornanen 2017). In contrast to mammals, no specialized ventricular conducting system has been morphologically identified in fish hearts, although optical mapping of ventricular excitation suggests the presence of a conducting pathway that regulates the rate and direction of impulse spread across the ventricle (Vornanen 2017).

The linkage of excitation of the cardiac myocyte SL to the contraction of the myofilaments is termed excitation–contraction (E–C) coupling (Shiels 2017). The same processes of E–C coupling that occur in mammalian cardiomyocytes occur in fish cardiomyocytes (Figure 4.3), but some notable distinctions exist. Fish cardiomyocytes have a large surface area to volume ratio compared with mammals. Consequently, trans-SL Ca²⁺ influx is the predominant (>85%) contributor to the intracellular Ca²⁺ transient [Ca²⁺]_i, with the majority of Ca²⁺ entering the cardiomyocyte through L-type Ca²⁺ channels, although reverse-mode Na⁺–Ca²⁺-exchanger (NCX) activity also contributes significantly to cardiac contractile Ca²⁺ in a number of species. Considerable variability in the role of the sarcoplasmic reticulum (SR) in cardiac contraction exists among and within fish species (Shiels and Galli 2014). In general, the contribution of SR Ca²⁺ to cardiac contraction is minimal to none in slow and sluggish fishes, whereas it plays a more important role in athletic fishes with a comparatively high f_H and P_VA (see Table 4.1 for definitions). Within a species, the contribution of SR Ca²⁺ to cardiac contraction is modulated by changes in temperature, contraction frequency, and adrenergic stimulation (e.g., Kubly and Stecyk 2019).

FIGURE 4.3 Excitation–contraction (E–C) coupling in fish cardiomyocytes. The primary source of the Ca²⁺ required for myofilament (i.e., cardiac) contraction is through L-type Ca²⁺ channels (LTCC). LTCCs open upon the depolarization of the sarcolemmal (SL) membrane, which is caused by the opening of voltage-gated Na⁺ channels (Na_V) and influx of Na⁺ (I_Na). In some species and under certain conditions, sarcoplasmic reticulum (SR) Ca²⁺ contributes to cardiac contraction. The opening of the SR Ca²⁺ release channels (the ryanodine receptors [RyR]) is triggered by Ca²⁺ entry into the cell. Additionally, Ca²⁺ influx via reverse-mode Na⁺/Ca²⁺-exchanger (NCX) activity and T-type Ca²⁺ channels (TTCC) can contribute significantly to cardiac contraction in some species. Myocardial relaxation occurs with the removal of Ca²⁺ from the cytosol by forward-mode NCX activity, the uptake of Ca²⁺ into the SR via the SR Ca²⁺-ATPase (SERCA), and supposedly less importantly, by the efflux of Ca²⁺ by the SL Ca²⁺-ATPase. Binding of adrenaline (Ad) to β-adrenergic receptors (β-AR) increases force of contraction by leading to increased influx of Ca²⁺ through LTCCs. Ad also decreases relaxation times in fish hearts, indirectly indicating that Ad stimulates increased uptake of Ca²⁺ into the SR by SERCA (via the phosphorylation of the accessory protein phospholamban [PLB] which causes it to lose its ability to inhibit SERCA). Repolarization of the SL membrane occurs by the efflux of K⁺ through various K⁺ channels, including the rapid (I_Kr) and slow (I_Ks) delayed-rectifier K⁺ channels and the background inward-rectifier K⁺ channel (I_K1). Na⁺/K⁺-ATPase (NKA) exchanges two K⁺ for three Na⁺ to maintain ion gradients.

The cardiovascular performance of fish is quantifiable through the measurement (and calculation) of numerous parameters. Table 4.1 summarizes and defines these parameters and provides the formulas to calculate them. Here, it is important to note that the formulas presented for calculating the vascular resistances (branchial, systemic, and total) and cardiac power output assume that central venous pressure (P_CV) is negligible, which is not always true (see Sandblom and Gräns 2017). Additionally, fish hearts have a remarkable ability to increase their force of contraction in response to increased venous return and filling pressure, which is termed the Frank–Starling response (Farrell and Smith 2017). Accordingly, venous filling pressure is directly related to stroke volume (Keen et al. 2017).

TABLE 4.1
Measured and Calculated Parameters Utilized to Quantify the Cardiovascular Performance of Fishes

4.2.4 Vasculature

Fish vasculature consists of five basic vessel types: arteries, arterioles, capillaries, venules, and veins. Arteries are conductance vessels distributing blood to the tissues. Composed of elastin, collagen, and smooth muscle, they also serve to dampen the pulse pressure with each heartbeat. Thus, they are also termed elastance or compliance vessels. The arterial system must balance tissue blood supply with tissue metabolic demands. Regulation of blood flow distribution primarily occurs at the level of small arteries and arterioles, termed resistance vessels, via dilation or constriction of the smooth muscle in the vessel wall (see Section 4.2.5). The capillaries (and some small arterioles and venules) are where gas and metabolites are exchanged. Capillaries are thin (4–10 μm in diameter) vessels composed of a single layer of endothelial cells with high surface area and low blood velocity to facilitate diffusion. Veins and venules return blood to the heart. These capacitance vessels act as a low-pressure, high-volume reservoir to store the blood volume. The venous system profoundly affects cardiac output by regulating blood flow returning to the heart and cardiac filling pressure (see Section 4.2.2). Comprehensive descriptions of fish vasculature anatomy have been provided elsewhere (Bushnell et al. 1992; Satchell 1992; Sandblom and Gräns 2017).

From the heart, all blood travels via the ventral aorta to the gills, which function in gas exchange (Chapter 3), osmo- and ionoregulation (Chapter 5), acid–base balance, nitrogen excretion, hormone metabolism, and the sensing of internal and external environments (Figures 4.4 and 4.5). Blood flows into several pairs of afferent branchial arteries (ABA), which enter the gill arches. Afferent filamental arteries (AFA) branch off the ABA to supply blood to the gill filaments. Blood travels from the AFA through the afferent lamellar arteriole, into the respiratory lamellae for gas and ion exchange, and then back out via the efferent lamellar arteriole through the efferent filamental artery to the efferent branchial artery (EBA). This arterio-arterial (i.e., respiratory) pathway of blood flow in fish gills is a highly effective countercurrent system, where blood flows in the opposite direction to water to maximize oxygen uptake into the lamellae (Figure 4.5). A small portion (<10%) of blood that exits the lamellae re-enters the filament and is directed to the nutrient circulation via nutrient arteries or into the intralamellar vasculature. The coronary arteries typically originate from the EBA and transport blood back to the myocardium of the conus arteriosus, ventricle, and atrium, depending on the type of heart (see Section 4.2.2) (Icardo 2017). The EBA pairs converge with the dorsal aorta and carotid arteries to supply oxygenated blood to the systemic circulation (Figure 4.4). Blood is distributed to the systemic tissues via arteries that branch from the dorsal aorta, which runs along the vertebrae towards the tail (Figure 4.4). Once the dorsal aorta exits the peritoneal cavity, it is known as the caudal artery. For the most part, a corresponding vein is closely associated with each artery. Veins draining the head and skin deliver blood to the sinus venosus and ducts of Cuvier. All other blood travels through portal systems, whereby blood travels first through one capillary bed in the tissues and then through another capillary bed before returning to the heart.

FIGURE 4.4 Schematic of the water-breathing teleost circulatory system. See Section 4.2.4 for details.
(Adapted from Sandblom, E. and Gräns, A., in Fish Physiology, Volume 36, Part A, The Cardiovascular System: Morphology, Control and Function, Academic Press, Cambridge, MA, 2017.)

FIGURE 4.5 Schematic of blood flow through the gill. The countercurrent arrangement of the capillary bed and water flow (blood flows in the opposite direction to water) allows highly efficient oxygen uptake.
(Adapted from Olson, K.R., J. Electron. Microsc. Tech., 19, 389–405, 1991.)

Fish have two portal systems: the hepatic portal system and the renal portal system (Figure 4.4). As in other vertebrates, the hepatic portal system drains blood from the stomach, intestines, spleen, and liver through the hepatic portal vein into the sinusoidal capillaries of the liver and back out through the hepatic veins to the sinus venosus. The renal portal system is unique to fishes; blood draining the trunk muscles, tail, and skin via the caudal vein, as well as the post-abdominal region (e.g. bladder and gonads), travels through the kidney before returning to the heart via the ducts of Cuvier.

Some fishes have evolved accessory pumps to help propel blood back to the main heart (Farrell 2011). Hagfish have a portal heart associated with the hepatic portal vein to assist blood flow from the intestines to the liver (Farrell 2007b). The portal heart is comprised of true cardiac muscle and is myogenic; thus, it generates an independent electrocardiogram. Caudal pumps have been discovered in hagfish, eels, and a few species of sharks (Farrell 2011). Though evolutionarily and morphologically distinct across groups, in all three groups, skeletal muscle serves as an accessory pump to enhance venous return. Branchial pumps take advantage of the gill muscles and rhythmic ventilation cycle to improve venous return to the heart.

A variety of fishes have a specialized structure termed a vascular rete, where arterial vessels are arranged in the opposite direction to venous vessels to allow countercurrent exchange of heat or gas (Figure 4.6) (Wittenberg and Wittenberg 1974; Stevens 2011). The swimbladder vascular retia secrete oxygen into the swimbladder to contribute to buoyancy. Fish eyes are avascular; thus, the eyes of most fish have a vascular rete (termed a choroid rete mirabile) that secretes oxygen into the eye to support aerobic metabolism. Heat-exchanging vascular retia are rarer. They are found in only ~30 species of fish, including tunas, some billfishes, some sharks, and the opah (Lampris guttatus) (Bushnell et al. 1992; Graham and Dickson 2001; Wegner et al. 2015). These heat exchangers can be found in the eyes, brain, muscles, gills, and viscera and function to conserve metabolic heat. As a consequence, fish with heat-exchanging retes are regional endotherms (part of their body is warmer than the environment).

FIGURE 4.6 Vascular retia showing countercurrent exchange of heat or gas. (a) A typical circulation pattern for most fishes. Metabolic heat produced in the tissues is lost at the gills. (b) The circulation pattern for countercurrent heat exchangers where metabolic heat is conserved in the tissues where it is produced. (c) Countercurrent gas exchanger serving the swimbladder. (d) Countercurrent gas exchangers serving the eye.
(Adapted from Wittenberg, J.B. and Wittenberg, B.A., Biol. Bull., 146, 116–136, 1974.)

The secondary circulation system is unique to fishes (Steffensen and Lomholt 1992; Rummer et al. 2014). It consists of a vascular network of arteries, capillaries, and veins that is derived from and runs in parallel with the primary circulation but contains few RBCs. Bony (teleost) fishes are considered to have two secondary circulations. In the first, secondary vessels typically derive from the dorsal aorta or segmental arteries, and the vessels are associated with the skin, scales, fins, mouth, and peritoneum. Notably, the secondary system is not associated with skeletal muscle or the gastrointestinal system, kidney, liver, swimbladder, brain, or eye. The other secondary circulation is located in the gills and is composed of two distinct vascular pathways: the nutrient pathway and the interlamellar pathway (described earlier). The function of the secondary circulation is poorly understood. Though morphological and molecular similarities between the vertebrate lymphatic system and the secondary system in zebrafish have been noted (Yaniv et al. 2006), the secondary vascular system does not appear to function like a mammalian lymphatic system (i.e., it does not assist with fluid balance). Historically, the secondary circulation system was assumed to play a negligible role in gas exchange given the paucity of RBCs, but it has been suggested to play a role in skin oxygen uptake, immune protection, acid–base regulation and ion transport, and reduction in cardiac work and RBC turnover (Steffensen and Lomholt 1992; Rummer et al. 2014).

4.2.5 Control Systems

Regulation of the fish cardiovascular system occurs primarily through the action of the autonomic nervous system, with the exception of hagfishes, in which nervous control of the circulatory system appears to be absent (Sandblom and Axelsson 2011; Farrell and Smith 2017; Sandblom and Gräns 2017). The autonomic nervous system consists of two opposing pathways: a parasympathetic vagal inhibitory component and a sympathetic (adrenergic) excitatory component. Cardioinhibitory parasympathetic control via the cardiac branch of the vagus nerve is the predominant form of f_H regulation in teleosts. The sympathetic component is of paramount importance for the regulation of blood pressure, cardiac contractility, and distribution of blood flow among vascular beds. Adrenergic stimulation of the cardiovascular system in teleosts occurs through both neuronal and humoral means. The catecholamines adrenaline and noradrenaline, liberated from the post-ganglionic terminals of sympathetic nerves near their site of action, evoke rapid responses in effector tissues. A more widely distributed adrenergic response occurs through catecholamine release directly into the bloodstream from chromaffin cells. These cells are localized within the walls of the posterior cardinal vein and in close proximity to the lymphoid tissue in the region of the anterior (head) kidney.

Since signaling molecules such as catecholamines cannot penetrate the cell membrane, a transduction pathway is needed for transmembrane signaling. Transmembrane signaling begins with the binding of catecholamines to cell-surface adrenoceptors, of which two main types, α and β, have been identified in teleosts. However, the location of each type varies among species (Sandblom and Axelsson 2011). Usually, α-adrenoceptors are in the vascular smooth muscle of arterioles, and β-adrenoceptors are found in the heart, vascular smooth muscle, and RBCs. Adrenergic stimulation typically results in an α-adrenergically mediated systemic vasoconstriction and β-adrenergically mediated increases in cardiac inotropy (force) and chronotropy (rate). A β-adrenergic vasodilatory effect can also occur in the arterioles of the systemic circulation but is often masked by the more potent α-vasoconstriction. In addition, in some fish, stimulation of cardiac α-adrenoceptors mediates negative chronotropy and inotropy (Stecyk 2017). Adrenergic stimulation of the branchial vasculature also exists in teleosts (Sandblom and Axelsson 2011). In contrast to the systemic circulation, the β-adrenergic-mediated vasodilatory response dominates in the gill respiratory (i.e., arterio-arterial) vasculature (Sandblom and Gräns 2017). In RBCs, the β-adrenergic response is crucial for maintaining or even enhancing oxygen delivery to tissues in time of stress. Briefly, catecholamines stimulate the activation of Na⁺/ H⁺ exchange across the erythrocyte membrane, which increases RBC intracellular pH relative to the plasma, thereby facilitating oxygen binding.

In addition to autonomic control, a plethora of circulating (humoral) and local (autocoid and paracrine) biochemical factors, hormones, and gasotransmitters play fundamental roles in fish cardiovascular control (Imbrogno and Cerra 2017; Sandblom and Gräns 2017). These include angiotensin II and natriuretic peptides, which participate in homeostatic circuits that integrate myocardial stretch and ion, water, and hemodynamic homeostasis; the derived peptides from the prohormone chromogranin-A (i.e., vasostatin and catestatin), which serve as cardiovascular stabilizers; and the endogenously produced membrane-permeable gases carbon monoxide, hydrogen sulfide, and nitric oxide, which exhibit neuroactive and vasoactive properties and also play a role in oxygen sensing (Perry and Tzaneva 2016). Finally, metabolic end-products, namely lactate ions, have been recently shown to elicit cardiorespiratory responses via stimulation of oxygen-sensing cells in the gills (Thomsen et al. 2019).

4.3 Integrative Cardiovascular Function

4.3.1 Exercise

Cardiovascular responses to swimming in fishes have been well studied (Farrell and Smith 2017). During aerobic swimming, Q ˙ steadily increases with increasing swimming speeds, reaching 60–300% higher than resting values. The relative contribution of f_H and V_S to the increased Q ˙ is species specific. For example, tuna rely primarily on f_H to increase Q ˙ during swimming (Farrell 1996), whereas salmonids increase V_S ~twofold but f_H usually only increases by ~50% (Eliason et al. 2013). During swimming, f_H increases primarily via a release of vagal cholinergic cardiac tone (i.e. removal of the cardiac brake) and also via increasing sympathetic adrenergic stimulation (i.e. pressing on the cardiac accelerator) (Farrell and Smith 2017). Stroke volume increases via increased adrenergic stimulation via the Frank–Starling effect (see Section 4.2.3) as well as via mobilization of blood from capacitance vessels (Farrell and Smith 2017; Sandblom and Gräns 2017). The consequence of the increased Q ˙ is increased O₂ delivery to the swimming muscles. Additionally, because the heart does not have the capacity to simultaneously perfuse all capillary beds, blood flow is redistributed during swimming to prioritize the perfusion of aerobic muscles and the coronary circulation (when present; see Section 4.2.2). An exciting area of current research includes the examination of how the Root effect (pH-dependent reduction in the O₂ carrying capacity of teleost hemoglobins) enhances O₂ delivery to metabolically active tissues (Harter and Brauner 2017) and the role of plasma accessible carbonic anhydrase in enhancing oxygen delivery to actively respiring tissues, such as the avascular spongy myocardium, during swimming (Alderman et al. 2016). Other current active areas of research consider how the cardiovascular system in swimming fishes responds to external stressors such as hypoxia, temperature changes, and toxicants.

4.3.2 Digestion

During digestion, oxygen consumption (termed specific dynamic action [SDA] or heat increment of feeding; see Chapter 6) increases substantially to support nutrient digestion, absorption, distribution, and processing. Concomitantly, gut blood flow (GBF) increases 40–150% from resting levels (30–40% of Q ˙ ; Farrell et al. 2001) to support nutrient, hormone, and waste transport and to supply oxygen to the respiring intestinal tissues. The increased GBF is achieved via an increase in Q ˙ and/or a redistribution of regional blood flow to the stomach and intestinal tissues (Seth et al. 2010). Although several studies have focused on the mechanisms of GBF control and coordination (Seth et al. 2010), in general, regional blood flow and tissue prioritization remains an understudied area. However, the influence of exercise on GBF has been examined in a few species. In unfed fish, GBF decreases during swimming, presumably to prioritize oxygen delivery to the swimming muscles. However, in some species, GBF in fed fish is spared to maintain blood flow to the intestines (e.g. salmonids; Thorarensen and Farrell 2006). In contrast, GBF decreases during swimming in fed sea bass (Altimiras et al. 2008; Dupont-Prinet et al. 2009). Several studies have examined how environmental factors (e.g. temperature, hypoxia, hypercapnia, salinity, and acute stress) influence GBF (Farrell et al. 2001; Seth et al. 2010). Given the importance of digestion for a fish’s ability to grow and thrive, the influence of climate change on the integrated cardiovascular response during digestion is likely to be a fruitful area of future research.

4.3.3High Temperature

An extensive literature has considered how increasing temperature (across both acute and acclimation time scales) influences cardiovascular variables in fishes (Eliason and Anttila 2017). Broadly speaking, Q ˙ increases with warming temperatures, which is almost exclusively driven by an increase in f_H (Eliason and Anttila 2017). In recent years, the heart has emerged as a potential mediator of thermal tolerance in fishes (Wang and Overgaard 2007; Farrell et al. 2009). Accordingly, one of the most active research areas in the field today seeks to determine why fish hearts fail at high temperature. One leading possibility is that the ion channels involved in E-C coupling become functionally impaired at elevated temperatures, which would compromise the spread of the action potential across the heart and reduce f_H (Vornanen 2017). One study with brown trout (Salmo trutta fario) found that Na⁺ channels were the most temperature sensitive (Vornanen et al. 2014). Another possibility is that mitochondrial function could become impaired at high temperature, causing a limitation in ATP supply for the heart (Eliason and Anttila 2017). Mitochondria become more permeable at elevated temperatures, reducing the efficacy of ATP production (Iftikar et al. 2014). Another hypothesis suggests that insufficient oxygen supply to the myocardium at high temperature may lead to cardiac collapse. As temperatures increase, partial pressure of oxygen in the venous blood decreases (Eliason and Anttila 2017), which could compromise oxygen delivery to the avascular spongy myocardium. In species with a coronary circulation, coronary blood flow has been demonstrated to play a role in thermal tolerance (Ekström et al. 2017). Coronary blood flow increases during warming, which would enhance cardiac oxygenation (particularly when oxygen delivery to the spongy myocardium is compromised by reduced venous oxygen levels) (Ekström et al. 2017). Moreover, cardiac myoglobin levels were correlated with upper thermal tolerance in Atlantic salmon (Anttila et al. 2013), which further supports the notion that oxygen supply does play a role in cardiac thermal tolerance. Finally, a noxious venous blood environment at high temperature could compromise cardiac contractility. As temperatures rise, blood pH decreases (acidosis), and plasma K⁺ increases (hyperkalemia). Acidosis and hyperkalemia (and hypoxia) have negative ionotropic and chronotropic effects on the heart (Hanson et al. 2006). Notably, adrenergic stimulation is critical to stimulate and protect the heart under these noxious conditions (Hanson et al. 2006), but the sensitivity of the heart to adrenaline decreases with warming in some species (Keen et al. 1993). Indeed, cardiac thermal performance varies across populations of sockeye salmon, which has been linked to the density of adrenaline-binding ventricular β-adrenoceptors (Eliason et al. 2011) and potentially Ca²⁺ cycling (Anttila et al. 2019). Thus, the role of the adrenaline signal transduction pathway in cardiac thermal tolerance remains a dynamic area of future research (Ekström et al. 2014; Gilbert et al. 2019).

4.3.4 Low Temperature

For freshwater fish that experience near-freezing temperatures in winter, cardiac physiology must be adjusted to accommodate the cold temperature–driven effects on cardiac excitability and contractility, blood viscosity, and associated vascular resistance (Vornanen 2016, 2017). The physiological strategy employed by fishes in response to cold temperature acclimation (or acclimatization) varies among species and is reflective of their overwintering strategy (Vornanen 2016; Stecyk 2017). As summarized in Table 4.1, some species, such as rainbow trout (Oncorhynchus mykiss) and burbot (Lota lota), exhibit physiological compensation that allows the continuation of an active lifestyle at cold temperature. By comparison, species that experience prolonged periods of oxygen deprivation during the winter months, such as the crucian carp (Carassius carassius), must prime physiological processes to conserve ATP, making positive compensatory changes maladaptive. Accordingly, for these species, cold exposure serves as an important cue to reduce activity, metabolic rate, and subsequently cardiac activity in anticipation of winter hypoxic and/or anoxic conditions (Vornanen et al. 2009; Stecyk 2017). The phenomenon is termed inverse thermal acclimation. Despite these general distinctions, some cardiophysiological responses to cold are shared across overwintering strategies. For example, both rainbow trout and crucian carp exhibit increased density of K⁺ currents in the heart with cold acclimation, and the Alaska blackfish (Dallia pectoralis) displays a combination of down-regulatory and cold-compensatory responses to cold acclimation (Kubly and Stecyk 2015, 2019). Finally, it is becoming increasingly recognized that naturally occurring seasonal acclimatization induces more pronounced changes in cardiac function than laboratory-based thermal acclimation (Filatova et al. 2019).

4.3.5 Limiting Oxygen Levels

Hypoxia and anoxia are prevalent in a wide range of aquatic systems, both naturally and due to anthropogenic causes (Diaz and Breitburg 2009). For many water-breathing fish, the premier cardiovascular response to aquatic hypoxia is a cholinergically mediated reflex slowing of f_H (termed hypoxic bradycardia). Hypoxic bradycardia is mediated through the activation of O₂ chemoreceptors located in the gills; in most species, these chemoreceptors sense and respond to changes in oxygen in the inspired water (Milsom 2012). Although hypoxic bradycardia is hypothesized to have several direct benefits to the heart (reviewed by Farrell 2007a), variation exists among species with regard to the water oxygen level at which hypoxic bradycardia is initiated as well as in the magnitude of f_H depression. In fact, some species do not always exhibit hypoxic bradycardia (e.g., rainbow trout, winter flounder, Pseudopleuronectes americanus, and Atlantic cod, Gadus morhua; see Stecyk 2017), whereas others do not exhibit hypoxic bradycardia at all (e.g., red- and white-blooded Antarctic fishes) even if exposed to anoxia (e.g., crucian carp) (Stecyk et al. 2004; Stecyk 2017). The variability relates to differences in ecology, lifestyle, and hypoxia tolerance, but intra-specific differences could also reflect differences in experimental design (Gamperl and Driedzic 2009). The typical cardiac response of air-breathing fish with biomodal respiration when exposed to aquatic hypoxia is a cycling of bradycardia prior to an air breath and a subsequent transient tachycardia (increase in heart rate) that commences with or just after each air breath (Graham 1997; Stecyk 2017). In addition to bradycardia, typical cardiovascular responses to hypoxia exposure include increased R_gill, P_DA, and R_sys in water-breathing teleosts but unchanged or decreased P_DA and R_sys in elasmobranchs (see Table 4.1 for definitions) (Stecyk 2017). In air-breathing fish, the prevailing response to aquatic hypoxia exposure with continued access to atmospheric air is an increase in Q ˙ , augmented blood flow to the air-breathing organ, and decreased blood flow to the gills (Stecyk 2017). Nevertheless, despite these general trends, it is becoming increasingly clear that the cardiovascular responses to oxygen deprivation are highly variable among and even within species.

Table 4.2 Comparison of the Cardiac Phenotypic Changes in Response to Cold Acclimation in Cold-Active and Cold-Dormant Fishes

4.4 Conclusion and Future Cardiovascular Research

Given the essential role the fish cardiovascular system plays in gas exchange, osmo- and ionoregulation, reproduction, endocrinology, digestion, immune function, locomotion, and in some fish species, thermal regulation, it is unsurprising that this critical organ system has received an enormous amount of research attention over the last century. In the current era of climate change and anthropogenic stressors, there is an intense focus on discovering the mechanisms that determine environmental tolerance limits (e.g. temperature, hypoxia, and toxicants). Moving forward, technological advances (e.g. smaller, cheaper, and longer-lasting biologgers and telemetry for cardiovascular measurements) will enable more research to transition from the laboratory to the field. The fish cardiovascular system is also increasingly being used as a model for human cardiac development and function as well as a tool to investigate questions relevant to human health and various oxygen deprivation–related diseases.

Acknowledgments

The research of E.J.E. is currently supported by the University of California, Santa Barbara and the Hellman Fellows Fund. The research of J.A.W.S. is currently supported by the National Science Foundation, Division of Integrative Organismal Systems. The authors gratefully acknowledge Paul Parsons for creating all the figures.

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