Exercise and the Coronary Circulation

Dirk J. Duncker , ... M. Harold Laughlin , in Muscle and Exercise Physiology, 2019

22.2.4.1 Systolic Compression of Intramyocardial Vessels

Cardiac contraction impedes coronary flow during the systolic phase so that under basal resting conditions arterial inflow occurs principally during the diastolic phase of the cardiac cycle. Measurements of epicardial coronary artery inflow under resting conditions in swine (Sanders et al., 1978; Bender et al., 2010) and dogs (Khouri et al., 1965), show that only 15%–20% of left ventricular flow occurs during systole (Fig. 22.3). However, the high heart rates produced by exercise result in progressive encroachment of systole on the diastolic interval, while absolute blood flow rates during systole increase. Consequently, as much as 40%–50% of total coronary arterial inflow can occur in systole during heavy exercise (Khouri et al., 1965; Sanders et al., 1978). The increase in the CBF fraction during the systolic phase has implications for the transmural distribution of myocardial blood flow, as the compressive effects of myocardial contraction on intramural coronary microvessels are not exerted uniformly across the left ventricular wall (Fig. 22.5). Thus, myocardial compressive force increases from intrathoracic pressure at the epicardial surface to equal or to exceed intraventricular pressure at the endocardial surface (Brandi and McGregor, 1969; Archie, 1978). Interaction of this gradient of tissue pressure with the intravascular distending pressure creates an array of vascular waterfalls across the left ventricular wall that particularly impedes subendocardial blood flow during systole (Downey and Kirk, 1975; Hess and Bache, 1976; Duncker et al., 1998a; Kajiya et al., 2000). Furthermore, as the contracting myocardium compresses the intramural vessels during each systole, blood from coronary microvessels within the innermost myocardial layers is pumped retrogradely into more superficial subepicardial and epicardial coronary arteries. Consequently, subendocardial vessels need to be refilled in diastole, analogous to the emptying and recharging of a capacitor (Hoffman and Spaan, 1990; Kajiya et al., 2000; Westerhof et al., 2006). Therefore, epicardial artery inflow during systole is directed toward the subepicardium, while antegrade subendocardial blood flow is confined exclusively to diastole. Furthermore, as the exercise-induced tachycardia leads to a shortening of diastole, a relatively greater part of diastole is required to refill the subendocardial vessels, thereby delaying net forward flow into the subendocardial microvessels. To study the effects of the increased force of cardiac contraction and increased heart rate during exercise, maximum coronary vasodilation of the coronary circulation is required to negate the confounding influence of metabolic vasoregulation of coronary resistance vessel tone, thereby allowing selective study of the impeding effects of myocardial contraction. Using this approach, Duncker et al. (1998a) observed that exercise caused a redistribution of blood flow toward the subepicardium away from the subendocardium (Fig. 22.4), consistent with the concept of the intramyocardial pump (Hoffman and Spaan, 1990). Despite the impeding effects of myocardial contraction on blood flow to the deeper myocardial layers during exercise, it should be noted that in the normal heart with intact coronary tone a modest net transmural gradient of blood flow favoring the subendocardium exists, which reflects the higher systolic tensions and O2 requirements of the innermost layers (Weiss, 1979). Maintenance of this normal pattern of transmural perfusion requires augmentation of subendocardial blood flow during diastole in proportion to the degree of systolic underperfusion. This diastolic gradient of blood flow, in turn, depends on a transmural gradient of vascular resistance, with resistance during diastole being lowest in the subendocardium (Bache and Cobb, 1977).

Figure 22.5. Graph showing a schematic drawing of the intramyocardial microvasculature (A) and the extravascular forces acting on the coronary microvasculature during diastole (B) and systole (C). P IM , Intramyocardial pressure; P LUMEN , pressure in left ventricular lumen; P PERI , pressure in pericardial space; P VEIN , venous pressure. See text for further explanation.

 Modified from Duncker, D.J., Bache, R.J., 2008. Physiol. Rev. 88, 1009–1086 with permission.

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hERG (Human Ether-a-Go-Go Related Gene)

Jill Steidl , in Encyclopedia of Toxicology (Second Edition), 2005

Introduction

Cardiac muscle contraction is an electrical event initiated at the sinoatrial node. Each cardiac muscle cell fires an action potential as a result of excitation propagated from the sinoatrial node, which produces muscle cell contraction. A wave of action potentials spreads across the organ to produce coordinated contraction of the heart and efficient ejection of blood to the body. Excitation and the subsequent return of a cardiac muscle cell to rest (repolarization) during the action potential is dictated by the flow of ions across the cell membrane. Membrane repolarization is produced by the flow of potassium ions through various types of potassium channels.

hERG (human ether-a-go-go related gene; KCNH2) encodes for the ion channel that underlies the rapidly activating delayed rectifier potassium current, I Kr. The hERG current (I Kr) is critical for ventricular repolarization in humans. Inhibition of hERG currents can induce QT prolongation, which is associated with induction of the potentially fatal ventricular arrhythmia Torsade de Pointes. A wide range of pharmaceutical agents from a variety of chemical classes have been found to inhibit hERG currents and produce QT prolongation and/or Torsade de Pointes, resulting in labeling revisions or withdrawal from the market.

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What Causes a Broken Heart—Molecular Insights into Heart Failure

Seán P. Barry , Paul A. Townsend , in International Review of Cell and Molecular Biology, 2010

5.1 How Ca2+ regulates cardiac myocyte contraction

Cardiac muscle contraction and heartbeat is regulated by a process known as excitation–contraction coupling (ECC). During systole, depolarization of the plasma membrane opens LTCCs, causing an influx of a small amount of Ca2+ into the cell. This in turn induces release of a large amount of Ca2+ from the SR via the ryanodine receptor in what is known as Ca2+-induced Ca2+ release. Soon after, intracellular Ca2+ levels rise 10-fold (from 100   nM to 1   μM) to the levels needed to bind toponin C and induce the conformational change necessary to promote actin–myosin crossbridge cycling (Frank et al., 2003; Maclennan and Kranias, 2003). At the start of diastolic relaxation, Ca2+ dissociates from troponin C, followed by reuptake into the SR through the SR Ca2+-ATPase 2 (SERCA2) and transsarcolemmal removal via the Na2+/Ca2+ exchanger (NKX; Chakraborti et al., 2007). Heart rate is also regulated through the SERCA2 inhibitor phospholamban (PLB) which is a major target of adrenergic signaling (Maclennan and Kranias, 2003). Thus a tightly controlled cycle of Ca2+ entry and release precisely regulates beat to beat oscillations in cardiac cells.

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Inherited Diseases of Ion Transport

Robert A. Farley , in Cell Physiology Source Book (Fourth Edition), 2012

VI Long QT Syndrome

Cardiac contraction is the end result of action potentials that are initiated at the sinoatrial node by the spontaneous depolarization of the nodal cells to threshold and the subsequent transmission of triggered action potentials in different cells of the cardiac conduction pathway to the atrial and ventricular muscle fibers. The amount of charge that moves across cell membranes during action potentials in most cells of the conduction system is small; however, because atrial muscle and ventricular muscle are sufficiently massive, charge movement during contraction and relaxation of these tissues can be detected at the surface of the body. It is the movement of charge during cardiac muscle contraction and relaxation that is measured in the electrocardiogram (EKG; ECG). A 12-lead EKG from a heart showing normal sinus rhythm is shown in Fig. 30.1A. The deflections are most easily identified using lead II, shown in Fig. 30.1B.

FIGURE 30.1. Electrocardiogram (EKG) showing normal sinus rhythm. (A) 12-lead EKG record. The horizontal axis is time and the vertical axis is voltage. Each lead is identified below the EKG trace that is recorded from that lead. (B) EKG trace from lead II in (A) showing the names of the deflections and intervals.

 (See text for details.)

The deflections or waves in the EKG correspond to atrial muscle depolarization and contraction (P wave), ventricular depolarization and contraction (QRS complex) and ventricular repolarization and relaxation (T wave). Among the parameters that are measured on an EKG are the times between specific events, such as the beginning of the T wave and the end of the R wave (PR interval) and the beginning of the Q wave and the end of the T wave (QT interval). In the normal population, the PR interval is 0.12–0.20   s. The QT interval is most often reported as a "corrected" QT interval, QT/√RR, in recognition of the fact that the QT interval changes as heart rate changes. Corrected QT intervals in the normal population are less than 0.44   s. When the QT interval is longer than 0.44   s, individuals are said to have long QT syndrome.

The presence and timing of the different deflections on the EKG reflect the highly coordinated opening and closing of ion channels in the cardiac myocytes. A typical action potential in ventricular myocytes is shown in Fig 30.2, with the different phases of the action potential labeled as phases 0–4. In the EKG, the QRS complex corresponds to muscle depolarization and contraction, or phase 0 in the action potential, whereas the T wave corresponds to muscle repolarization and relaxation, or phase 3 of the action potential.

FIGURE 30.2. Drawing of an action potential from a cardiac ventricular myocyte. The phases of the action potential are identified by the numbers 0–4. The value of the membrane potential is shown on the vertical axis as a function of time on the horizontal axis.

 (See text for details.)

The phase 0 depolarization of the action potential is due to the opening of voltage-gated Na+ channels that are encoded by the SCN5A gene. These channels inactivate toward the end of phase 0 and, in phase 1, the reduction in sodium conductance due to the closure of these channels, together with the delayed opening of transient-open K+ channels, is responsible for the slight repolarization of the membrane potential that is observed. During phase 2 of the action potential, there is a relative balance between inward current carried primarily by Ca2+ and Na+ ions through voltage-gated L-type Ca2+ channels and outward current through delayed rectifier K+ channels. Toward the end of phase 2, the voltage-gated Ca2+ channels close while delayed rectifier K+ channels continue to activate, shifting the balance of current flow to outward K+ current. This shift in charge movement repolarizes the membrane potential and triggers muscle relaxation. On the EKG, the QT interval can be understood as a reflection of the balance between the depolarization due to open Na+ channels and repolarization due to open K+ channels. Mutations in any of the channels that affect the action potential duration might be expected to affect the QT interval and at least 10 forms of long QT syndrome have been identified in patients, reflecting underlying mutations in these different channels or other proteins associated with them.

Long QT syndrome type 1 (LQT1) is due to mutations in the KCNQ1 gene that encodes the pore forming α subunit of the slow delayed rectifier K+ channel. In phase 2 of the action potential, two different delayed rectifier K+ channels open at different rates, a fast delayed rectifier and a slow delayed rectifier. The slow delayed rectifier channel consists of a pore forming α subunit (KvLQT1) and a β subunit (MinK) that is encoded by the KCNE1 gene. LQT5 is caused by mutations in the KCNE1 gene. The faster-opening delayed rectifier K+ channel contains a pore-forming α subunit that is encoded by the HERG gene and a β subunit (MiRP1) encoded by the KCNE2 gene. LQT2 is due to mutations in the HERG gene and LQT6 is caused by mutations in the KCNE2 gene. A different type of K+ channel, an inward rectifier K+ channel, plays little or no role during phase 2 of the cardiac action potential, but is important during the phase 3 repolarization phase. The current carried by these channels is called IK1 and is due to the inward rectifier Kir2.1 channel that is encoded by the KCNJ2 gene. Reductions in IK1 prolong the repolarization phase of the action potential and mutations in KCNJ2 underlie LQT7. As discussed in the next section, Kir2.1 K+ channels are also expressed in skeletal muscle and mutations in KCNJ2 lead to a form of periodic paralysis in skeletal muscle that is called Andersen's syndrome (Andersen–Tawil syndrome). All of the forms of long QT syndrome that are caused by mutations in genes encoding K+ channel subunits are loss-of-function mutations that lead to reductions in repolarizing currents. This reduction in repolarization prolongs phase 2 of the action potential, which is manifest as a longer QT interval on the EKG.

In contrast to the loss-of-function mutations in K+ channels, mutations in the SCN5A gene encoding the voltage-gated Na+ channel that are associated with LQT5 are gain-of-function mutations. These mutations do not alter the conductance of the channel but rather affect the inactivation of the channel. Electrophysiological measurements and computer simulations of channel activity show that a small fraction of voltage-gated Na+ channels with LQT5 mutations reopen during phase 2 of the action potential and result in a sustained inward Na+ current. This inward Na+ current is depolarizing and opposes the repolarization that is due to opening of K+ channels.

Other forms of long QT syndrome have been identified in which mutations occur in genes that encode other proteins that influence the action potential, such as voltage-gated Ca2+ channels or proteins that affect the subcellular localization of the channels, such as ankyrin. The molecular characterization of the effects of these mutations has not been so well characterized, however, as those described above.

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Cardiac Arrhythmias

James W. Little DMD, MS , ... Nelson L. Rhodus DMD, MPH , in Little and Falace's Dental Management of the Medically Compromised Patient (Eighth Edition), 2013

Etiology

Cardiac contractions are controlled by a complex system of specialized excitatory and conductive neuronal circuitry (Figure 5-1). The normal pattern of sequential depolarization involves the structures of the heart in the following order: (1) sinoatrial (SA) node, (2) atrioventricular (AV) node, (3) bundle of His, (4) right and left bundle branches, and finally (5) subendocardial Purkinje network. 13 The electrocardiogram (ECG) is a recording of this electrical activity. The primary anatomic pacemaker for the heart is the SA node, a crescent-shaped structure 9 to 15 mm long that is located at the junction of the superior vena cava and the right atrium. The SA node regulates the functions of the atria and is responsible for production of the P wave (atrial depolarization) on the ECG (Figure 5-2). The ends of the sinus nodal fibers connect with atrial muscle fibers. The generated action potential travels along the muscle fibers (internodal pathways) and eventually arrives at and excites the AV node, which serves as a gate that regulates the entry of atrial impulses into the ventricles. It also slows the conduction rate of impulses generated within the SA node. From the AV node, impulses travel along the AV bundle (His bundle) within the ventricular septum, which divides into right and left bundle branches. The bundle branches then terminate in the small Purkinje fibers, which course throughout the ventricles and become continuous with cardiac muscle fibers. Simultaneous depolarization of the ventricles produces the QRS complex on ECG. The T wave is formed by repolarization of the ventricles. Repolarization of the atria occurs at about the same time as depolarization of the ventricles and thus is usually obscured by the QRS wave. 13

Normal cardiac function depends on cellular automaticity (impulse formation), conductivity, excitability, and contractility. Disorders in automaticity and conductivity constitute the underlying cause of the vast majority of cardiac arrhythmias. Under normal conditions, the SA node is responsible for impulse formation, resulting in a sinus rhythm with a normal rate of 60 to 100 beats per minute. 14 However, other cells or groups of cells also are capable of generating impulses (ectopic pacemakers), and under certain conditions, these may emerge outside of the normal conduction system. After a normal impulse is generated (depolarization), cells of the SA node need time for recovery and repolarization and are said to be refractory; during this time, they cannot conduct an impulse. Disturbances causing complete refractoriness result in a block, and those inducing partial refractoriness result in delay of conductivity.

Disorders of conductivity (block or delay) paradoxically may lead to rapid cardiac rhythm through the mechanisms of reentry. Reentry arrhythmias occur when accessory or ectopic pacemakers reexcite previously depolarized fibers before they would become depolarized in the normal sequential impulse pathway, typically producing tachyarrhythmias. The type of arrhythmia may suggest the nature of its cause. For example, paroxysmal atrial tachycardia with block suggests digitalis toxicity. 14 However, many cardiac arrhythmias are not specific for a given cause. In such cases, a careful search is undertaken to identify the cause of the arrhythmia. The most common causes include primary cardiovascular disorders, pulmonary disorders (e.g., embolism, hypoxia), autonomic disorders, systemic disorders (e.g., thyroid disease), drug-related adverse effects, and electrolyte imbalances. 3,15 Cardiac arrhythmias also are associated with many systemic diseases (Table 5-1) and various drugs or other substances including foods 3,14,16,17 (Table 5-2).

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Cardiac Injury, Maladaptation, and Heart Failure Incidence

M. Wesley Milks MD , Vijay Nambi MD, PhD , in Biomarkers in Cardiovascular Disease, 2019

Cardiac Troponins

Myocardial contraction occurs at the myofibrillar level by regulated interactions between actin and myosin. Cardiac troponins (cTns) serve various roles in such regulation, including troponin C (cTnC) in calcium binding, troponin I (cTnI) in inhibition, and troponin T (cTnT) in tropomyosin binding. 78 Proteins cTnT and cTnI can be released in patients with HF in the absence of an acute coronary ischemic event or underlying epicardial coronary artery stenosis. Subendocardial ischemia is thought to play a central role in this process. 79 Troponin assays have typically been used as part of the diagnosis of myocardial infarction in the emergency department or hospital. Recently, higher sensitivity cTn assays that have a 10-fold or greater sensitivity have been developed and quantitate the cTn level when it exceeds the 99th percentile of a reference population. 80 High-sensitivity (hs) assays can now quantitate cTn in 50% to greater than 95% of healthy individuals. 81

cTns are now supported by a robust evidence basis in the prediction of HF. 82 In individuals at risk for HF (stage A HF) or asymptomatic individuals with ventricular dysfunction (stage B HF), cTn is detectable by standard modern assays in 1%–5% 83 and in 50%–80% with hs assays. 84,85 Importantly, elevated (≥0.003   ng/mL) hs-cTnT concentrations have a stronger association with risk of incident HF (HR 5.95) rather than ischemic events (HR 2.29), as was demonstrated by Saunders et al. in an analysis of the Atherosclerosis Risk in Communities (ARIC) Study (Table 8.1). 85 Similarly, in the Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE) trial, elevation of hs-cTnT in a general population with stable CAD was associated with HF and CV death but not with MI. 86 In the Cardiovascular Health Study (CHS), which included adults aged   ≥   65   years, hs-cTnT was measured at baseline and 2–3   years later; patients with the highest baseline hs-cTnT had the highest risk of incident HF, and there is a stepwise increase in adverse CV events when hs-cTnT exceeds 0.003   ng/mL 84,85,87 . Trends among repeated cTn values may carry particularly strong prognostic weight. In the CHS, among individuals with initially detectable hs-cTnT, a subsequent increase of more than 50% was associated with an increased risk for HF (adjusted HR [aHR] 1.61) and cardiovascular death (aHR 1.65), whereas a decrease of more than 50% was associated with a reduced risk of these outcomes (HF aHR 0.73, cardiovascular death aHR 0.71). 84

It is noteworthy that cardiac troponin is also associated with other HF risk factors, such as increasing age, hypertension, diabetes, chronic renal failure, and LV hypertrophy. 83,88 Troponin elevation in kidney disease is particularly complex given that different cTn isoforms may demonstrate variable renal clearance, with cTnT felt to exhibit more dependence on renal clearance than cTnI, and that there is heterogeneity in renal clearance among different breakdown fragments of each isoform. 82,89,90 Despite some limitations, cardiac troponins remain a cornerstone of the prediction of HF using circulating biomarkers. In addition to de novo HF risk prediction, there is some evidence that trends in cTn values may be reliable for revised predictive estimates in the face of therapeutic lifestyle changes. An analysis of the CHS showed that higher physical activity was associated with reduced odds (odds ratio 0.50 [95% CI 0.33–0.77]) of cTnT increases as well as lower long-term incidence of HF. 91

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hERG (Human Ether-a-Go-Go Related Gene)

J Steidl-Nichols , in Encyclopedia of Toxicology (Third Edition), 2014

Introduction

Cardiac muscle contraction is an electrical event initiated at the sinoatrial node. Each cardiac muscle cell fires an action potential as a result of excitation propagated from the sinoatrial node, which produces muscle cell contraction. A wave of action potentials spreads across the organ to produce coordinated contraction of the heart and efficient ejection of blood to the body. Excitation and the subsequent return of a cardiac muscle cell to rest (repolarization) during the action potential is dictated by the flow of ions across the cell membrane. Membrane repolarization is produced by the flow of potassium ions through various types of potassium channels.

hERG (human ether-a-go-go related gene, KCNH2) encodes for the ion channel (Kv11.1) that underlies the rapidly activating delayed rectifier potassium current, IKr. The intriguing gene name comes from its discovery in fruit fly (Drosophila melanogaster) experiments. In the 1960s, a drosophila mutant was discovered that showed leg-shaking behavior when placed under ether anesthesia. Since the flies appeared to be doing a go-go dance (a phenomenon of the 1960s), the fly mutation and gene locus were creatively named ether-a-go-go. The shaking behavior was due to enhanced excitability at the neuromuscular junction because of impaired repolarization of the nerve terminal and enhanced neurotransmitter release, suggesting defective potassium conductance. The ether-a-go-go gene was subsequently cloned from drosophila, and the cloning of related DNA sequences from mammalian species soon followed and included hERG (human ether-a-go-go related gene). Electrophysiological recordings from Xenopus oocytes expressing the hERG protein demonstrated a potassium current with properties nearly identical to that of the IKr potassium current previously described in human cardiac myocytes, thus linking hERG to the human cardiac current.

The hERG current (IKr) is critical for ventricular repolarization in humans. Inhibition of hERG currents can induce a delay in ventricular repolarization, which is evidenced by QT prolongation on an electrocardiogram (ECG). QT prolongation is associated with induction of the arrhythmia torsade de pointe, a polymorphic ventricular tachycardia that can degenerate into ventricular fibrillation and sudden death. Human genetic mutations in hERG manifest in a prolongation of the QT interval, are classified as long QT syndrome 2 (LQT2) and are associated with the increased risk of torsade de pointe and sudden death.

QT prolongation due to hERG inhibition frequently occurs with antiarrhythmic therapies (e.g., almokalant, amiodarone, disopyramide, dofetilide, procainamide, quinidine, sotalol) and contributes to the efficacy of these compounds by making the heart resistant to abnormal electrical activity. For many patients, the benefit of increased survival outweighs the risk of torsade de pointe, but these agents carry strong warnings of the risk of arrhythmia and death.

A wide range of marketed noncardiac drugs have also been found to inhibit hERG currents and produce QT prolongation, and in some cases produce an increased risk for torsade de pointe. This side effect is extremely undesirable for drugs designed to treat non–life-threatening diseases, and has resulted in drug labeling revisions or withdrawal from the market. For example, cisapride is a drug that was approved in 1993 for treatment of gastroesophageal reflux disease (GERD). It was a very effective drug for the treatment of GERD, and had reached nearly 1 billion dollars in annual worldwide sales by 1999. However, over that course of time, postmarketing data accumulated demonstrating that cisapride increased the frequency of QT prolongation and sudden death associated with ventricular arrhythmia. By 2000, it was withdrawn from the market with more than 300 reports of QT prolongation or ventricular arrhythmia including torsade de pointe and 80 deaths. Cisapride-induced QT prolongation was attributed to block of the hERG potassium current, and in vitro experiments demonstrated that cisapride inhibited hERG currents at concentrations of the drug typically experienced by humans at recommended dose levels.

Many other marketed drugs have since been found to prolong the QT interval and pose a risk for induction of torsade de pointe. These findings triggered labeling revisions including black box warnings, and in some cases, withdrawal from the market. The agents were identified from a variety of therapeutic indications, indicating a widespread problem that could not be isolated to a single chemical class. Some examples include terfenadine and astemizole (antihistamines); clarithromycin, erythromycin, and fluconazole (anti-infectives); sertindole and thioridazine (antipsychotics); and terodiline (urinary antispasmodic). In order to avoid this issue in the future, the pharmaceutical industry has developed methods to proactively address the risk of hERG inhibition for drugs in the discovery pipeline, and now characterize the potential for hERG inhibition and QT prolongation before new drugs are ever tested in humans.

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Cardiovascular Toxicity of Cardiovascular Drugs

Ramachandran Meenakshisundaram , ... Ponniah Thirumalaikolundusubramanian , in Heart and Toxins, 2015

8.2 Normal Cardiac Contraction

Normal cardiac contraction is vital to maintain cardiovascular health and prevent CVDs. Cardiac contraction depends on the maintenance of a normal sinus rhythm and atrioventricular (AV) as well as inter- and intraventricular synchronization of activation, along with the integrity of the cardiac conduction pathway and well-organized excitation–contraction coupling. For adequate cardiac function, a rhythmic contraction and a forceful extrusion of blood is achieved through careful structural organization of sequential contractions. 2 The contraction of cardiomyocytes is accomplished by a process that is called excitation–contraction coupling.

Action potential plays a key role in initiating, coordinating, and regulating this process, and therefore is at the core of cardiac function. This in turn is mediated by voltage-gated ion channels that selectively allow respective ion movements across the cellular membrane down their electrochemical gradient. 3 The cellular membrane is the key regulating element of the conductance of these voltage-gated ion channels and is thereby the driving force of the cardiac action potential. Subtle changes in transmembrane voltage can influence ion channel activation and inactivation ports and can rapidly change their confirmation, altering conductance of the ion channel and subsequently changing ionic currents and transmembrane voltage. This in turn influences the conductance of other ion channels and their respective ionic currents, giving rise to an electrical cascade known as an action potential.

In order to coordinate cardiomyocytes' contraction throughout the heart, action potentials need to be propagated between cells through gap junctions. Gap junctions are specialized structures consisting of collections of intercellular channels that connect adjacent cells in numerous tissues and organs and allow chemical and electrical communication. In the heart, they provide the path for intercellular current flow that is the result of rapid sodium (Na+) influx during excitation and intracellular Na+ rises. This passage of Na+ ions depolarizes the cardiac myocytes beyond the excitation threshold and evokes excitation in the cell, thereby facilitating coordinated action potential propagation.

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Signal Analysis

Franklin Bretschneider , Jan R. de Weille , in Introduction to Electrophysiological Methods and Instrumentation, 2006

The Electroencephalogram

Like heart activity, electrical processes from the brain can be recorded from the outside. In this case, however, one does not record from a "single unit". To the contrary, the electroencephalogram (EEG) is the ultimate of gross-activity recording. Electrodes on the scalp, usually an array of a dozen or more, will record the average activity of millions of neurons, from large parts of the brain. Nevertheless, a functional segregation of brain functions can be made by choosing electrode positions carefully. The waveforms recorded now do not reflect the spike frequencies of some brain cells, but rather the degree (and timescale) of synchronization of large populations of brain cells. If all brain cells would fire uncorrelated, the result would again be a form of shot noise treated earlier, and so would show an almost "white" spectrum (the bandwidth limited mainly by the spectral contents of spikes). This is not the case with the EEG, where often a single frequency (or a narrow band of frequencies) is most prominent. Even in the earliest EEG records, made by Berger in the 1920s, a few prominent frequencies can be seen (see Fig. 4-31). These rhythms were designated Greek letters, which in part are still in use today: the alpha rhythm, around 10 Hz, during resting when awake; the beta rhythm (wideband, irregular) when performing mental tasks; delta waves (about 4 Hz) during deep sleep. All in all, EEG signals span a frequency band of about 1 to 50 Hz.

Fig. 4-31. (A) An EEG by Berger of his 15-year-old son, together with a 10 Hz reference signal (lower trace). (B) Amplitude spectrum (0–50Hz) computed from the graph, showing peaks at about 1 and 10 Hz.

 From Berger, H. (1929). Copyright © 1929

EEG electrodes are usually somewhat smaller than their ECG counterparts (often small metal discs with or without silver chloride coating), but are still large enough to have a fairly low impedance (a few kΩ at 50 Hz). Gain demands for an EEG amplifier are however very high, because the signal is usually only a few tens of μV in amplitude. Limiting the bandwidth with higher-order filters is also important.

Both time domain and frequency domain are important for the processing of EEG signals. Like cardiograms, EEGs are usually analysed visually by an expert. Some types of EEG show characteristic patterns called "spindles" in the time domain, where the amplitude is waxing and waning gradually. In addition, the amplitude spectrum, obtained by Fourier-transforming the encephalic signal, may give additional cues.

The EEG described so far is a spontaneous activity of the brain, depending in a global way on the mental state of the subject. Responses to sensory stimuli, which may give more specific answers as to sensory processing, can also be recorded. However, since the EEG stems from a huge number of neurons, responses to specific stimuli are usually too weak to be recognized from a single record. This is why such evoked potentials, more generally dubbed event-related potentials (ERPs), only become visible after substantial signal averaging (the event is not necessarily a sensory stimulus: it can also be a motor action of the subject). Of course, the averaging can be triggered on a fixed point, such as the start of the stimulus (an acoustical beep, a light flash, a brief touching of the skin, etc.) or the command for an action. An example is shown in Fig. 4-12. Averaging some 64–256 sweeps usually reveals a significant electrical response. Size, latency and other quantities may then be related to the processing of the stimulus in question by the brain.

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Cardiovascular Toxicology

R.J. Sommer , in Comprehensive Toxicology, 2010

6.04.2.4 Relaxation of Contraction

Relaxation of myocardial contraction is achieved by multiple processes which serve to reduce the cytosolic concentration of Ca2+ back to resting levels. First, Ca2+ influx is mostly terminated by inactivation of ICaL during the plateau (phase 2) of the AP. L-type Ca2+ channels undergo Ca2+-dependent inactivation, most likely mediated by calmodulin binding to the pore-forming region of the L-type Ca2+ channel (Bodi et al. 2005). Second, a combination of RyR2 inactivation and partial depletion of SR Ca2+ stores turns off Ca2+ release from the SR (Bers 2002). Third, the Ca2+-ATPase pump of the SR (SERCA2) removes most of the elevated Ca2+ from the cytoplasm. SERCA2 uses ATP to pump Ca2+ back into the SR where it is reversibly buffered by the Ca2+-binding protein, calsequestrin.

SERCA2 activity is regulated by the phosphorylation state of the protein phospholamban (PLB), an SR membrane protein (Simmerman and Jones 1998). Phosphorylation of PLB by any of several kinases relieves PLB's inhibition of SERCA2, enhancing Ca2+ sequestration in the SR. Fourth, proteins present on the sarcolemma serve to transport Ca2+ out of the cell. The primary transport system for the efflux of Ca2+ from myocardial cells is the NCX which uses the Na+ gradient to transport three Na+ ions into and one Ca2+ ion out of the cell (Sheu and Blaustein 1992). Finally, there are also the ATP-dependent Ca2+ pump (Carafoli 1987) and mitochondrial Ca2+ uniporter (Gunter et al. 1994; Maack and O'Rourke 2007) that move small amounts of Ca2+ outside of the cell and into the mitochondria, respectively. As the cytosolic concentration of Ca2+ decreases, Ca2+ dissociates from Tn C, reestablishing the tropomyosin blockade of actin and myosin binding, leading to muscle relaxation and diastole.

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