Which electrolyte imbalance at the cellular level causes changes in the normal conduction and contractile function of the myocardium?

Increases in Ventricular Contractility Cause Decreases in Ventricular End-Systolic Volume

Contractility refers to the pumping ability of a ventricle. With increased contractility, there is a more complete emptying of the ventricle during systole and therefore a decreased end-systolic volume. An increase in contractility brings about an increase in stroke volume without requiring an increase in end-diastolic volume (see Fig. 21.2, middle). Fig. 21.5 shows graphically that an increase in contractility brings about an increased stroke volume for any given end-diastolic volume.

Sympathetic nerve activity increases ventricular contractility through the action of the neurotransmitter norepinephrine, which activates β-adrenergic receptors on ventricular muscle cells. As discussed in Chapter 19, activation of β-adrenergic receptors leads to an increased influx of extracellular Ca2+ into cardiac cells during an action potential (and to several other effects); the overall result is that cardiac contractions are stronger, quicker to develop, and shorter. Epinephrine and norepinephrine released from the adrenal medulla and circulating in the blood can likewise activate β-adrenergic receptors and increase contractility, as can β-adrenergic agonist drugs (e.g., isoproterenol). The cardiac glycosides (e.g., digitalis) are another class of drugs that increases cardiac contractility, again by increasing the cytosolic Ca2+ concentration during an action potential.

If cardiac contractility becomes depressed, there is less-than-normal ventricular emptying during systole. End-systolic volume increases and (as shown in Fig. 21.5) stroke volume decreases. A decrease in sympathetic activity causes a decrease in cardiac contractility, as do β-adrenergic antagonist drugs (e.g., propranolol or atenolol), which block the β-adrenergic receptors on cardiac muscle cells. As with β-adrenergic antagonists, calcium channel–blocking drugs also decrease cardiac contractility by making less Ca2+ available for the activation of the contractile proteins. Barbiturates, opioids, and some general anesthetics depress cardiac contractility as well; this must be kept in mind, particularly when administering such drugs to a patient who may already have compromised cardiac function. A decrease in cardiac contractility causes a decrease in stroke volume and therefore cardiac output. Consequently, the patient's blood pressure may fall to dangerously low levels.

A decreased cardiac contractility is the hallmark of the clinical condition called myocardial failure, which can result from coronary artery disease, myocardial ischemia, myocardial infarction, myocarditis, toxins, or electrolyte imbalances. Myocardial failure impairs the pumping ability of one or both ventricles. Myocardial failure is one subtype of the more general dysfunction called heart failure (pump failure), which is the term that encompasses any dysfunction in the heart that compromises the heart's ability to supply the systemic organs with the blood flow they need to support their metabolism. Heart failure can also be caused by structural abnormalities in the heart (e.g., defective cardiac valves). Valvular heart disease will be described subsequently.

Although ventricular contractility is usually the predominant factor affecting ventricular end-systolic volume, the effect of arterial blood pressure must also be considered. A substantial increase in arterial blood pressure impairs ventricular ejection because the left ventricular pressure during systole must exceed aortic pressure before ejection of blood from the ventricle can occur. The pressure that a ventricle must generate in order to eject blood is called cardiac afterload. The higher the afterload, the more difficult it is for the ventricle to eject blood. If arterial pressure is excessively high, ventricular ejection is impaired, end-systolic volume increases, and stroke volume decreases. This effect is minor for a normal heart that is operating within the normal range of arterial pressure. However, high afterload can significantly limit stroke volume for a heart that is in failure.

Introduction

Contractility is an essential property of all types of muscles. This feature enables the heart to produce the power necessary for its pump function. At the cellular level, muscle contraction is regulated through a process referred to as excitation–contraction coupling (EC coupling). This process starts with an action potential (AP) in the cell membrane (excitation) followed by a series of steps that link the AP-mediated excitation to commencement of contractile work (Figure 12.1). Central to the EC coupling process is an increase in cytoplasmic free [Ca2+] ([Ca2+]i). Cellular Ca2+ handling is a highly controlled process that involves ion exchange systems, ion pumps, and specialized compartments for Ca2+ storage within the cell. In this chapter, the general principles of cardiac EC coupling, and how this involves Ca2+ fluxes, will be outlined.

Poor Contractility

Poor contractility is suspected when the preload parameters (history of recent fluid loading, ease of jugular vein distention, central venous pressure, postcaval diameter, end-diastolic ventricular volume) suggest normal or high preload and the forward flow parameters (blood pressure, pulse quality, indicators of vasomotor tone [capillary refill time], and indicators of tissue perfusion [appendage temperature, metabolic acidosis, lactate level, central venous oxygen pressure]) suggest poor cardiac out in an animal without organic heart disease (e.g., hypertrophic cardiomyopathy, mitral insufficiency, aortic stenosis, pericardial tamponade, fibrosis). If poor contractility is suspected, administration of a β1 agonist is indicated. If the animal is also hypotensive, dopamine (5 to 20 mcg/kg/min) is recommended; if blood pressure is acceptable, dobutamine (5 to 20 mcg/kg/min) is recommended.

2. Contractility

Cardiac contractility is a term that expresses the vigor of contraction or, more specifically, the change in developed force at a given resting fiber length (Berne and Levy, 1988). An increase in fiber length above resting increases the force of contraction (Frank–Starling mechanism), but it does not increase contractility. Measures of contractility in vitro include peak isometric tension and maximal shortening velocity at a fixed initial length. Measurement of contractility in vivo is less precise. The dP/dt during the isovolumic phase of the cardiac cycle (isometric contraction) and initial velocity of blood flow in the aorta are used as indirect indices. Davie et al. (1987) noted that dP/dt values for ventricular contractions in teleosts ranged from 370 mm Hg/sec to 480 mm Hg/sec, about five times slower than those of mammalian hearts. On the other hand, tunas have higher heart rates and ventral aortic pressures, and dP/dt values are much higher compared with other teleosts, falling into the mammalian range (Jones et al., 1992). In contrast, ventricular dP/dt for Myxine glutinosa and Eptatretus cirrhatus (approximately 22 mm Hg/sec) is more than 10 times slower than that for teleosts (Davie et al., 1987). Ventricular dP/dt in the leopard shark (Triakis semifasciata) is also slow (25 mm Hg/sec), increasing to only 36 mm Hg/sec during swimming (Lai et al., 1990a). The slow dP/dt in hagfish and elasmobranchs probably reflects low contractility and perhaps slow rates of electrical conduction between myocytes. Slow conduction rates would be expected in hagfish because of the lack of deeply penetrating T tubules in the SL and poor electrical couplings between myocytes (Davie et al., 1987).

Neural (vagal and adrenergic nerve fibers), humoral, and local factors can increase (positive inotropy) and decrease (negative inotropy) cardiac contractility. Among the specific factors known to increase contractility of the atrium and/or ventricle in fishes are the following: increased temperature (Ask et al., 1981; Bailey and Driedzic, 1990), β-adrenergic stimulation (see Ask et al., 1981; Laurent et al., 1983; Nilsson, 1983; Farrell, 1984; Vornanen, 1989), the peptides arginine vasotocin and oxytocin (Chui and Lee, 1990), adenosine (Lennard and Huddart, 1989), prostacyclin (Acierno et al., 1990), and histamine (Temma et al., 1989). Negative inotropic effects on atrial or ventricular tissue occur with the following: hypoxia and acidosis (Gesser and Poupa, 1983; Farrell, 1984), acetylcholine (Randall, 1970; Holmgren, 1977; Cameron and Brown, 1981), α-adrenergic stimulation in some species (Tirri and Lehto, 1984), purinergic agents (Meghi and Burnstock, 1984), and adrenaline in combination with adenosine (Lennard and Huddart, 1989). Isolated atrial and ventricular tissues can have different sensitivities to pharmacological agents. For example, acetylcholine has negative inotropic effects on the Atlantic cod atrium but not on the ventricle, whereas the ventricle is more sensitive to adrenergic stimulation (Holmgren, 1977). This implies that vagal innervation is confined to the atrial region. Interestingly, the affinity for β-adrenergic atrial stimulation is greater in Platichthys flesus and Squalus acanthias (fish without adrenergic innervation) than in rainbow trout (Ask, 1983).

Contractility, as measured by the force of contraction of cardiac muscle strips in vitro, is dependent on the duration of the active state (the period of contraction and relaxation) and its intensity (rate of contraction). The relationship between maximal isometric force and contraction frequency is documented for several species. In ventricular and atrial strips from hagfish (Myxine glutinosa) and a variety of teleost species, an increase in contraction frequency reduces the duration of the active state, decreases maximal isometric tension, and, at higher frequencies, the rate of contraction (Ask, 1983; Driedzic and Gesser, 1985; Vornanen, 1989). This inverse relationship between maximal isometric tension and contraction frequency for these teleosts and hagfish is referred to as a negative staircase effect. In other vertebrates, including ventricular tissue from mammals and several elasmobranch species (Driedzic and Gesser, 1988) and atrial tissue from skipjack tuna (Keen et al., 1992), there is a positive relationship between contraction frequency and maximal isometric tension at low frequencies, whereas at higher frequencies the relationship is again negative. Thus, the force–frequency relationship has an apex, i.e., a contraction frequency at which maximal isometric tension reaches a peak. In elasmobranchs, the apices occur at contraction frequencies (0.3–0.4 Hz) that correspond to in vivo heart rates. Similarly, the apex for skipjack tuna (1.4–1.6 Hz) also corresponds to in vivo heart rates. Moreover, skipjack atrial tissue can contract up to a maximal frequency of 3.4 Hz (Keen et al., 1992), a frequency that is well beyond those reported for other fish species. The relevance of these in vitro observations to the relationships between maximal isometric tension, contraction frequency, and the duration of the active state to the in vivo situation is further brought home by Vornanen's observation that the duration of the action potential is very similar to the duration of contraction.

In electrically paced cardiac strips in vitro, increasing temperature increases the rate of contraction, thereby increasing contractility (Ask, 1983). However, the duration of the active state is shorter, with increasing temperature through shorter contraction and relaxation times (Vornanen, 1989; Bailey and Driedzic, 1990), and this reduces maximal isometric tension. Nonetheless, because the active state is shorter, the muscle strips can contract at higher frequencies at high temperatures. An additional effect of temperature is revealed in spontaneously beating cardiac strips in vitro; the negative staircase effect is less pronounced at high than at low temperatures because the higher heart rates result in a shorter active state. Some of the changes in cardiac contractility associated with temperature acclimation were identified by Bailey and Driedzic (1990). Among these were a pronounced reduction in the duration of relaxation (e.g., yellow perch, Perca flavescens) and a shorter-duration contraction (e.g., smallmouth bass, Micropterus dolomieui, and yellow perch) in cold-acclimated compared with warm-acclimated fish.

The positive inotropic effect of β-adrenergic stimulation is the result of increases in both the rate and duration of contraction in crucian carp and rainbow trout (Vornanen, 1989). Again positive chronotropy also caused by β-adrenergic stimulation offsets, but does not overcome, the positive inotropic effects (Ask, 1983). In contrast, adrenaline increased maximal tension independent of frequency in atrial strips from skipjack tuna; the duration of contraction increased with no change in the rates of contraction and relaxation (Keen et al., 1992).

Cardiac contractility in fishes is dependent on extracellular calcium concentrations, reflecting the overall importance of transsarcolemmal calcium movements in the availability of activator calcium for excitation–contraction coupling (see Chapter 6). In several species of elasmobranchs and teleosts, including skipjack tuna, maximal isometric force increases severalfold with increasing extracellular calcium (1–9 mM) (Driedzic and Gesser, 1985; Driedzic and Gesser, 1988; Keen et al., 1992). One consequence of the positive inotropic effect of extracellular calcium is to shift the relationship between maximal isometric tension and contraction frequency to the right (Driedzic and Gesser, 1988). Despite marked in vitro effects on contractility by extracellular calcium, in vivo effects may be quite limited because a reasonably good homeostatic mechanism maintains extracellular calcium levels above the threshold for major cardiac effects. An increase from 1 mM to 2 mM extracellular calcium substantially increased

Bladder

Bladder contractility is predominantly mediated by the parasympathetic nervous system. Specifically, main trunks of the pelvic nerve travel through the visceral pelvic fascia (otherwise known as the posterior endopelvic fascia) to the bladder and proximal urethra to provide the detrusor muscle with parasympathetic innervation (Hollabaugh et al., 2000). These fibers are preganglionic autonomic fibers that travel alongside the superior vesical vasculature and ultimately synapse with postganglionic fibers within the wall of the bladder (Hollabaugh et al., 2000). The course of these preganglionic pelvic nerve fibers traversing laterally from the pelvic floor over the rectal fascial investments en route to the bladder presents many potential sites for neural injury during pelvic surgery. Moreover, denervation or disruption of these neurons at any point in their course may result in autonomic dysfunction, which is most commonly manifested as denervation and areflexia of the detrusor muscle, with a clinical picture of postoperative urinary retention (Hollabaugh et al., 2000).

3.2 Incorporating Myosin II

Cellular contractility in nonmuscle cells is generated by the motor action of NMII exerted upon F-actin networks (Murrell, Oakes, Lenz, & Gardel, 2015). Consistent with this central cell-biological role, NMII is found decorating the medial–apical and junctional F-actin networks that are thought to exert contractile forces on cell–cell junctions (Mason, Tworoger, & Martin, 2013; Smutny et al., 2010). Considering that cadherin-bound actin filaments are the scaffolds upon which actomyosin is assembled, the incorporation of NMII at junctions involves two parallel processes.

First, NMII must be activated. A dominant pathway involves the phosphorylation of the regulatory light chain of myosin through pathways mediated by kinases such as myosin light chain kinase (MLCK) and Rho-dependent kinase (ROCK) (Heissler & Manstein, 2013). This is thought to promote F-actin binding, mini-filament assembly, and hence formation of an effective contractile unit. Consistent with this, both MLCK and ROCK support junctional contractility and the recruitment of NMII to the junctional cytoskeleton (Smutny et al., 2010) and to medial–apical networks (Mason et al., 2013; Munjal et al., 2015).

Second, activated NMII must interact with F-actin networks. Of note, cadherin junctions are sites of dynamic actin assembly, initiated by actin nucleators such as Arp2/3 and formins, and modulated by postnucleation regulators such as Ena/VASP proteins and α-actinin-4 (Ratheesh & Yap, 2012). Their contribution to recruitment of NMII is illustrated by evidence that inhibiting Arp2/3 or its upstream activator, WAVE2, impaired the junctional recruitment of NMII and reduced junctional tension (Verma et al., 2012). This implies that the assembly of actin filaments at the junctional cortex serves to recruit activated NMII to the junctions, thereby allowing the contractile apparatus to assemble. However, the role of nucleators such as Arp2/3 carries a potential paradox. Arp2/3 generates branched actin networks that are thought to be poorly fitted for either stable NMII binding or contractile force generation. In part, this is because NMII tends to cause severing of branched networks, thereby turning over the actin scaffolds necessary for stable NMII localization (Reymann et al., 2012). Despite this, the cell clearly has developed strategies that compensate for this potential paradox, which may include stabilization of nascent filaments (Kovacs et al., 2011; Wu et al., 2014) and reorganization of actin networks to allow them to better sustain contractile stress (Murrell et al., 2015). While many mechanistic details have yet to be resolved, these observations carry the important implication that regulation of junctional F-actin (kinetics, organization) may constitute a pathway to influence contractility that operates orthogonal to that of the classical mode of NMII activation.

Ventricular function assessment

Net systolic contractility of the left ventricle is of great prognostic value and powerfully defines cardiac event rates in hypertensive patients. The evolution of hypertensive heart disease from the state of hypertrophic changes (with generally well-preserved systolic contractility) is a complex process (see other chapters), with progressive change through to a phase of ventricular dilatation and systolic impairment. These patients tend to have unrecognized, untreated, or persistently uncontrolled hypertension, and the progression to systolic impairment of the heart is not often recognized short of acute presentation of pulmonary edema. The widely cited but poorly analyzed association of arterial hypertension to systolic left ventricular impairment suggests the presence of such a progressive change regardless of the definition or recognition of intervening coronary occlusion and ventricular infarction.

3.2.2 Cardiac Contractility

Myocardial contractility describes the performance of cardiac muscle and is defined as the intrinsic ability of a cardiac muscle tissue to contract at a given sarcomere length. Adjustment of cardiac contractility to new conditions happens at the level of individual myocytes in the properties of myofilaments or in the management of intracellular Ca2+ concentration. The duration of ventricular twitch, especially the relaxation phase, is much longer in winter-acclimatized crucian carp than in summer-acclimatized fish (Vornanen, 1994b), suggesting seasonal differences in cardiac contractility. The rate of cardiac contraction is determined by attachment and detachment rate of cross bridges, i.e., by myosin ATPase activity and by the rate of activation induced by Ca2+ ions and their removal (Hoh et al., 1988), and evidence is accumulating that both Ca2+ management and cardiac myosins are modulated by seasonal acclimatization in crucian carp. These changes probably contribute to the anoxia tolerance of the heart.

The force of cardiac contraction is directly related to the amount of free intracellular Ca2+. Electrical excitation of the sarcolemma grades the size of intracellular Ca2+ in a process of excitation-contraction (e-c) coupling to produce adequate amounts of force and power for pumping of blood (Bers, 2002). As a part of a physiologically integrated entity, contractility and e-c coupling of the fish heart must be fine-tuned to correspond to the overall physiological demands under varying environmental conditions, and accordingly we can expect modifications at the organ, cell, and molecular level in fish exposed to prolonged anoxia.

In most fish hearts, the major part of Ca2+ comes from the extracellular space through L-type Ca2+ channels and Na+–Ca2+ exchange (NCX), and may trigger a further release of Ca2+ from the sarcoplasmic reticulum (SR) via the SR Ca2+ release channels. Contraction ends when Ca2+ is returned from myofilaments back to the extracellular space and into the lumen of the SR by NCX and SR Ca2+-pump, respectively (Tibbits et al., 1992; Vornanen et al., 2002b; Hove-Madsen et al., 2003; Shiels and White, 2005). Sarcolemmal Ca2+ influx through both Ca2+ channels and NCX is critically dependent on the shape of AP, especially on plateau height and duration, and therefore any current that has influence on the shape of AP may affect voltage-dependent Ca2+ transport across the SL and, accordingly, e-c coupling (Edman and Johannsson, 1976). Function of the sarcolemmal K+ currents is especially important, since they regulate the duration of cardiac AP (Vornanen et al., 2002b; Schotten et al., 2007).

L-type Ca2+ current and NCX are the principal Ca2+ pathways in the crucian carp cardiac myocytes (Vornanen, 1997; Vornanen, 1999). Seasonal changes in the number of pore-forming alpha subunits of the L-type Ca2+ channels (DHPRs, dihydropyridine receptors) in crucian carp heart have been measured by [methyl-3H]PN200-110 binding (Vornanen and Paajanen, 2004) and show that the number of Ca2+ channels are approximately doubled for a relatively short period of time in mid-summer (May–July), i.e., for the major part of the year the density of Ca2+ channels is low (Figure 9.14). Furthermore, the change in the number of Ca2+ channels can be triggered by temperature acclimation (Tiitu and Vornanen, 2003). Functionally, these changes appear as 74% larger Ca2+ current (at 11 °C) in summer-acclimatized hearts in comparison to winter-acclimatized hearts, and when measured in seasonally relevant temperatures (4 °C and 18 °C) the current is 6.1 times larger in summer than in winter (Vornanen and Paajanen, 2004). Even if the lengthening of ventricular AP from about 1.3 s to 2.8 s in the cold (Paajanen and Vornanen, 2004) is taken into account, sarcolemmal Ca2+ influx through L-type Ca2+ channels is at least three times larger in summer than in winter.

Although seasonal changes in e-c coupling proteins of the crucian carp heart, except myosin heavy chains and L-type Ca2+ channels, have not been examined yet, temperature acclimation under laboratory conditions indicate that several ion transport mechanisms are depressed by cold-acclimation. The density of Na+ current, which determines the rate of impulse propagation in the heart, is strongly depressed to one-fifth of that of warm-acclimated fish with cold-acclimation (Haverinen and Vornanen, 2004). Thapsigargin (a specific blocker of SR Ca2+-pump)-sensitive Ca2+ uptake of the cardiac SR is also decreased in cold-acclimated crucian carp (Aho and Vornanen, 1998). Assuming that cold-acclimation primes the heart of crucian carp for winter, those findings suggest that several steps of the cardiac e-c coupling are down-regulated for winter and that the activity of the heart is depressed in the absence of positive thermal compensation in the cold winter waters. Indeed, tissue level experiments indicate that the kinetic properties of atrial and ventricular contraction are strongly depressed by cold-acclimation, which should appear as strongly reduced cardiac power output in the cold (Tiitu and Vornanen, 2001).

Interesting exceptions to the inverse thermal compensation of the crucian carp cardiac function are sarcolemmal K+ currents (Haverinen and Vornanen, 2008). Two major K+ currents of the fish heart are the inward rectifier K+ current (IK1), which maintains the negative resting membrane potential and contributes to the final rate of AP repolarization, and the rapid component of the delayed rectifier K+ current (IKr), which is important in the regulation of plateau duration (Vornanen et al., 2002a). Densities of these K+ currents are increased by cold-acclimation in atrial and ventricular myocytes of the crucian carp heart so that the sizes of the currents are similar in cold-acclimated fish at 4 °C and in warm-acclimated fish at 18 °C (Haverinen and Vornanen, 2008). Still, the duration of AP is 2.6 and 2.8 times longer at 4 °C than at 18 °C for ventricular and atrial muscle, respectively. Obviously positive temperature compensation in the density of K+ currents is not sufficient to prevent the lengthening of cardiac AP in winter.

Thus, our current knowledge of cardiac ion currents of the crucian carp indicates that the inward Na+ and Ca2+ currents are depressed and the outward K+ currents are enhanced in the cold-acclimatized winter fish. Inward currents are excitatory in that they promote contraction, while outward currents tend to stabilize membrane to the negative equilibrium potential of K+ ions. Therefore, opposite changes in inward and outward currents are likely to reduce excitability of the cardiac muscle.

Cardiac contractility is also affected by composition and function of myofibrillar proteins. Two myosin heavy chains have been demonstrated in crucian carp ventricle by SDS-PAGE (Vornanen, 1994b). Only one myosin heavy chain isoform is expressed in the hearts of winter-acclimatized fish and is therefore called “winter” myosin, whereas the hearts of summer-acclimatized fish express both winter and “summer” isoforms. In June and July both isoforms are almost equally represented in the ventricular muscle, but the amount of summer myosin decreases already in August and cannot be resolved any more in September. Small amounts of summer myosin appear again in May, when waters warm up (see Figure 9.2). The physiological significance of this seasonal pattern in myosin heavy chain composition probably lies in the different myosin-ATPase activities of the two isoforms: the activity is much greater in summer than in winter (Vornanen, 1994b; Tiitu and Vornanen, 2001). It is well known that the contraction of slow myosins occurs with less energy expenditure than the contraction of fast myosins (Alpert and Mulieri, 1982). Therefore, the exclusive reliance on the slow myosin in winter would improve energetic economy of the heart under conditions where energy production is severely limited by oxygen shortage. In heart function, this should appear as a reduced cardiac power output, which might be well tolerated due to reduced circulatory demands. The slow myosin may also be useful in tuning the rate of myofilament sliding to the low heart rate and the long duration of cardiac action potential in the cold. Taken together, inverse thermal compensation seems to be typical for the crucian carp, with the exception of sarcolemmal K+ currents, which will result in temperature-dependent depression of cardiac function in cold and anoxic winter waters.

3 Tissue invagination: Integrating cells across the tissue

Actomyosin contractility at the apical cortex generates forces that lead to apical constriction, but these cellular forces are also integrated across the tissue during tissue invagination (Harris & Tepass, 2010; Heisenberg & Bellaïche, 2013; Lecuit et al., 2011). Force transmission requires actomyosin to be mechanically linked to E-cadherin-containing adherens junctions (AJs) (Hoffman & Yap, 2015). In epithelia, AJs mediate cell adhesion, which is necessary to maintain the integrity of the tissue (Baum & Georgiou, 2011; Leckband & de Rooij, 2014). Cell adhesion is mediated by homotypic interactions of the extracellular cadherin domains (Leckband & Prakasam, 2006; Leckband & Sivasankar, 2012). The cytoplasmic tail of cadherins bind to α-, β-, and p120 catenins and the cadherin-catenin complexes mediate force-sensitive binding to the cytoskeleton with other accessory proteins (Harris & Tepass, 2010; Hoffman & Yap, 2015; Leckband & de Rooij, 2014; Lecuit & Yap, 2015). Furthermore, regulation of actomyosin at AJs plays an important role in maintaining strong cell adhesion and mechanosensitivity during cell rearrangements and tissue morphogenesis (Engl et al., 2014; Kovacs et al., 2002; Leerberg et al., 2014; Priya et al., 2015; Ratheesh & Yap, 2012).

At the onset of Drosophila mesoderm invagination, AJs shift from an initially sub-apical position to the apical surface in the mesoderm (Dawes-Hoang et al., 2005; Kölsch, Seher, Fernandez-Ballester, Serrano, & Leptin, 2007). The apical shift of E-cadherin clusters requires Traf4, a member of the tumor necrosis factor receptor-associated factor (TRAF) family (Mathew, Rembold, & Leptin, 2011), and also depends on apical actomyosin accumulation (Weng & Wieschaus, 2016). During mesoderm invagination, apical actomyosin networks connect with neighboring cells by attaching to apical E-cadherin clusters, forming a supracellular actomyosin network that can transmit forces across the tissue (Martin, Gelbart, Fernandez-Gonzalez, Kaschube, & Wieschaus, 2010; Sánchez-Corrales & Röper, 2018; Yevick, Miller, Dunkel, & Martin, 2019) (Fig. 2). Actomyosin at the apical cortex can form connections with AJs through direct physical interactions with α-catenin and vinculin (Buckley et al., 2014; Desai et al., 2013; Homem & Peifer, 2008; le Duc et al., 2010; Sako, Nagafuchi, Tsukita, Takeichi, & Kusumi, 1998; Yamada, Pokutta, Drees, Weis, & Nelson, 2005; Yonemura, Wada, Watanabe, Nagafuchi, & Shibata, 2010). In addition, the Afadin homologue Canoe (Cno) has been shown to localize to AJs and to mediate linkage to the actin cytoskeleton, a function that is required for apical constriction and convergent extension movements during Drosophila gastrulation (Sawyer et al., 2011; Sawyer, Harris, Slep, Gaul, & Peifer, 2009).

The importance of physically linking actomyosin to AJs is exemplified in embryos that are depleted for β-catenin (Armadillo, Arm) where myosin that is no longer tethered to intact AJs contracts at the apical cortex with no associated reduction in apical cell area (Dawes-Hoang et al., 2005; Martin et al., 2010). More recently, it was demonstrated that the connection between medioapical actin and the AJ is dynamic and that actin turnover repairs fractures between actomyosin and AJs as tension builds, which stabilizes actomyosin attachments to AJs over long time scales (Jodoin et al., 2015) (Fig. 2). Interestingly, without an organized microtubule cytoskeleton, separations of the apical F-actin meshwork from AJs are not repaired efficiently and lead to large apical actomyosin network fractures, suggesting that microtubules promote actomyosin reattachment to AJs (Ko et al., 2019).

The integration of contractile forces at the tissue surface is concomitant with the formation of a supracellular actomyosin network that leads to a buildup of epithelial tension. In the Drosophila mesoderm, tension is highest along the anterior-posterior axis, an anisotropy that is reflected in how ventral cells constrict (Chanet et al., 2017; Martin et al., 2010). Mesoderm cells constrict primarily along the dorsal-ventral axis and remain elongated along the anterior-posterior axis. Thus, tissue mechanics can bias the directionality of cell shape changes and the resulting deformations and curvatures that are associated with these cell shape changes (Fig. 3). In addition to active forces at the apical surface, passive mechanical forces also contribute to mesoderm invagination and internalization. Critically, during mesoderm invagination, ventral cells conserve their volume as they apically constrict, which is thought as being sufficient to generate invagination (Gelbart et al., 2012; Izquierdo, Quinkler, & De Renzis, 2018; Polyakov et al., 2014). Volume conservation results in a lengthening of lateral surfaces along the apical-basal axis (Costa et al., 1994; Gelbart et al., 2012). It has been suggested that apical-basal shortening and basal expansion after cell lengthening at later stages of ventral furrow formation comprises the final force that drives full mesoderm internalization (Conte et al., 2012; Sweeton et al., 1991). The mesoderm-specific disassembly of basal myosin coincides with basal expansion and invagination and is necessary for invagination (Krueger, Tardivo, Nguyen, & De Renzis, 2018; Polyakov et al., 2014). Finally, either pushing forces or mechanical compliance of the lateral and dorsal ectodermal tissues may play an important role during mesoderm internalization as increasing stiffness in these tissues prevents tissue invagination (Conte, Muñoz, Baum, & Miodownik, 2009; Perez-Mockus et al., 2017; Rauzi et al., 2015).

Cellular actomyosin contractility and force transduction through connections to AJs create a complex interplay of active and passive forces within the tissue that promotes tissue internalization. An additional level of regulation is conferred through mechanical feedback that fine tunes cellular response to force, such as by modulation of junctional strength. (Gomez, McLachlan, & Yap, 2011; Lecuit & Yap, 2015; Leerberg et al., 2014; Ratheesh & Yap, 2012). During mesoderm invagination, actomyosin contractility is responsible for protecting AJs against Snail-mediated disassembly, suggesting that contractility reinforces the coupling between cells (Weng & Wieschaus, 2016). Tissue mechanics can also influence cytoskeletal organization with actomyosin aligning with the axis that most greatly resists contraction (Chanet et al., 2017; Yevick et al., 2019) (Fig. 3). Finally, mechanical deformation of the embryo by a micromanipulation needle has been shown to be sufficient to induce apical myosin accumulation and to promote mesoderm invagination, suggesting the possibility that mechanical tissue deformations that occur as cells initiate constriction can feed back and further activate myosin, leading to more collective cell constrictions (Pouille, Ahmadi, Brunet, & Farge, 2009). Overall, studies of Drosophila gastrulation have illustrated how cell force generation can be modulated by mechanical and geometric properties of the tissue.

Pathophysiology

I.

Decreased contractility results in an increased end-systolic volume and reduced CO, leading to hypotension and activation of the β-adrenergic nervous system and RAAS.

The increased end-systolic volume results in increased LV diastolic filling pressure.

Increased preload leads to a compensatory, eccentric LV hypertrophy (increased end-diastolic diameter).

Left-sided CHF develops when LV end-diastolic pressure exceeds 20 to 25 mmHg.

When there is also right ventricular myocardial failure, right-sided CHF (ascites, hepatomegaly, pleural effusion, jugular venous distension) develops with right ventricular end-diastolic pressures ≥15 mm Hg.