The specialized electrical conduction system of the center allows for the synchronous contraction of the left and right sides of the heart and the sequential contraction of the atria and ventricles (Effigy 1).
From: Encyclopedia of Toxicology (Second Edition) , 2005
Cardiovascular System
P.A. Stapleton , ... T.R. Nurkiewicz , in Encyclopedia of Toxicology (Third Edition), 2014
Impulse Conduction
The specialized electrical conduction system of the heart allows for the synchronous contraction of the left and right sides of the eye and the sequential contraction of the atria and ventricles (Figure ane(b)). Electrical impulses most apace arise in the spontaneously firing cells of the sinoatrial (SA) node usually called the 'pacemaker.' The SA node is located at the junction of the superior vena cava and the right atrium. A wave of depolarization (see below) originating at the SA node is conducted first to the cells of the correct atrium, then to the cells of both atria, finally converging on a 2nd group of specialized cells – the cells of the AV node. These cells act as a conduit for the original impulse from the SA node to the AV node, which lies at the junction of the median wall of the right atrium and the septum separating the ii ventricles. From the AV node, the impulse wave next passes into the ventricular conduction system – the bundle of His and Purkinje fibers – located within the ventricular septum, which allows for the depolarization of ventricular musculus.
If a microelectrode is inserted into a resting muscle or nerve cell (termed 'excitable tissue'), an electrical potential difference will be recorded beyond the membrane of that cell. In the case of cardiac muscle cells, this resting potential is −ninety mV (intracellular relative to extracellular). In other words, the cell membrane is electrically polarized with the inwards facing surface of the membrane having a net negative charge with respect to the outer facing surface of the membrane. This polarity is maintained primarily by the presence of extracellular positively charged ions and intracellular negatively charged proteins. The flux of ions through active (requiring cellular energy) and passive (concentration-driven) processes is responsible for changes in electrical potential. In the resting cardiac musculus jail cell, the concentration of potassium ions (Yard+) is higher inside the prison cell than outside, while sodium ions (Na+) are at a much college concentration outside the jail cell than inside. Cellular energy is required to maintain the appropriate resting state distributions of the different ions across the jail cell membrane. In the case of M+ and Na+ ions, there is a prison cell membrane pump, which requires energy derived from the hydrolysis of the terminal phosphate grouping from adenosine triphosphate (ATP). The associated enzyme responsible for this hydrolysis is the Na+–K+ ATPase. When an electrical stimulus is received past a cardiac muscle prison cell, voltage-gated channels in the cell membrane open allowing Na+ to diffuse down its concentration and electrical gradients into the jail cell. This influx of positive charge causes the jail cell membrane to become 'depolarized' (i.e., to take less negative charge). As depolarization proceeds, the membrane may reach the threshold potential (−70 mV for near cardiac muscle cells). Whatever further depolarization results in a phenomenon known as the action potential, which completely depolarizes the cell. At the peak of the activity potential, the inside of the cell actually becomes positive relative to the exterior (+30 mV). The cell membrane then repolarizes relatively slowly and reaches the −xc mV resting potential before it tin respond to another electrical impulse. The wave of depolarization moves very apace across the membrane of an private cardiac muscle prison cell. In addition, the wave of action potentials is propagated to adjacent cells via the specialized gap junctions. This propagation allows for the complete depolarization of most cells in the network, thus initiating the wrinkle of the heart muscle as a group.
Cardiac muscle cells predominantly brandish a fast response activity potential (Figure two), and cells in the atria and ventricles exhibit a rapid conduction velocity due to the gap junctions. The depolarization–action potential–repolarization process is divided into 5 phases. Stage 0 begins when the threshold potential has been reached. At this time, many 'fast' Na+ channels in the cell membrane open allowing an inrush of Na+ ions to initiate the action potential. At the end of stage 0, the cell is completely depolarized. Toward the terminate of stage i and the start of phase two, the Na+ influx begins to decrease, as does the membrane potential. During the relatively long (200–300 ms) phase 2 plateau, calcium (Ca2+) and Na+ ions enter through 'slow' membrane channels. Movement of ions through these 'slow' channels simply takes place after the membrane potential has dropped to approximately −55 mV, that is, after the 'fast' Na+ ion current has ceased. While these 'tiresome' in currents occur, there is also a slow outward motion of K+ ions which keeps the plateau relatively steady. The Ca2+ influx of phase 2 triggers the process known as excitation–contraction coupling, in which the myosin thick filaments slide by the sparse actin filaments in the contractile unit of the muscle known as the sarcomere. This process requires free energy and involves activation of a myosin ATPase that hydrolyzes ATP. The released energy is utilized to form cross-bridges between the actin and myosin molecules. Both the velocity and the force of contraction are dependent on the corporeality of Ca2+ ions that reaches the site of contraction. Within the resting muscle cell, Catwo+ is sequestered in a compartment called the sarcoplasmic reticulum. During the action potential, Caii+ and Na+ ions that enter the cell cause depolarization of the sarcoplasmic reticulum membrane, resulting in the release of large amounts of Caii+, which are needed for effective contraction of the sarcomere. Betwixt contractions, Catwo+ is again sequestered in the sarcoplasmic reticulum so that the actin–myosin interaction is not overly prolonged. During the long duration of the plateau stage, a new action potential cannot be initiated because the 'fast' Na+ channels are inactivated or refractory to farther electric stimulation. During phase 3, membrane permeability to K+ increases and the 'tiresome' Ca2+ and Na+ channels go inactive. The ensuing efflux of Thou+ ions allows for repolarization of the membrane until the normal resting potential is reached (stage four).
Figure 2. The principal ionic movements during the unlike phases of the action potential in a cardiac muscle cell.
Reprinted with permission from Raffaele De Canterina, et al., 2003. Antiarrhythmic furnishings of omega-three fatty acids: from epidemiology to bedside. Am. Centre J. 146 (three), 240–430. http://world wide web.sciencedirect.com/science/commodity/pii/S0002870303003272
In contrast, conduction velocity is wearisome in musculus fibers at the SA and AV nodes. Unlike the majority of cardiac muscle cells, these pacemaker cells take an unstable resting potential (approximately −60 mV) due to a cell membrane alteration that allows Na+ ions to leak into the cell without a concurrent Grand+ ion efflux. This Na+ leakage reduces the membrane potential allowing even more Na+ ions to move into the jail cell. In addition to the inward Na+ motility, there is as well an inward Catwo+ flow which causes the pacemaker cells to have a more positive resting potential. Finally, the prison cell produces an action potential at approximately −40 mV. This phenomenon is called spontaneous diastolic depolarization. The overall effect is that pacemaker cells initiate waves of depolarization that move across the heart causing the muscle to contract. Every bit noted previously, this phenomenon occurs ∼72 times per minute (more than or less depending on autonomic nervous organization stimulation, periods of stress, or physical activity). The SA node is responsible for this charge per unit equally it depolarizes the fastest. The other nodes and components of the cardiac conduction may also drive depolarizations, only slowly. The purpose of this back-up is to ensure pacemaker activity in the heart (to support cardiac homeostasis). The waves of electrical action may be recorded in an electrocardiogram (ECG), which displays the cyberspace electric changes relative to where the recording electrodes are placed on the surface of the torso.
Sean G. Collins , Konrad J. Dias , in Acute Care Handbook for Physical Therapists (Fourth Edition), 2014
Electrophysiologic Studies
EPSs are performed to evaluate the electric conduction organisation of the middle.12 An electrode catheter is inserted through the femoral vein into the right ventricle noon. Continuous ECG monitoring is performed internally and externally. The electrode tin can evangelize programmed electrical stimulation to evaluate conduction pathways, formation of arrhythmias, and the automaticity and refractoriness of cardiac muscle cells. EPSs evaluate the effectiveness of antiarrhythmic medication and can provide specific information almost each segment of the conduction system.12 In many hospitals, these studies may be combined with a therapeutic process, such equally an ablation procedure (discussed in the Management department). Indications for EPSs include the following12:
•
Sinus node disorders
•
AV or intraventricular block
•
Previous cardiac arrest
•
Tachycardia at greater than 200 bpm
•
Unexplained syncope
Clinical Tip
Patients undergoing EPSs should remain on bed rest for 4 to 6 hours after the test.
Stuart 50. Linas MD , Shailendra Sharma MD , in Critical Intendance Secrets (Fifth Edition), 2013
21 What are the clinical manifestations of hyperkalemia?
Clinical manifestations of hyperkalemia are dependent on many other variables such as calcium, acid-base status, and chronicity.
The most serious manifestation of hyperkalemia involves the electrical conduction organisation of the middle. Profound hyperkalemia tin can lead to middle block and asystole. Initially, the ECG shows peaked T waves and decreased aamplitude of P waves followed past prolongation of QRS waves. With severe hyperkalemia, QRS and T waves blend together into what appears to be a sine-moving ridge blueprint consistent with ventricular fibrillation. A good way to call back about ECG changes in hyperkalemia is to imagine lifting the T wave, in which the T gets taller kickoff followed by flattening of P and QRS. Other furnishings of hyperkalemia include weakness, neuromuscular paralysis (without central nervous system disturbances), and suppression of renal ammoniagenesis, which may result in metabolic acidosis.
Alan C. Pao MD , Stuart Fifty. Linas Doc , in Critical Care Secrets (Fourth Edition), 2007
15 What are the clinical manifestations of hyperkalemia?
The nigh serious manifestation of hyperkalemia involves the electrical conduction system of the heart. Profound hyperkalemia tin can pb to heart block and asystole. Initially, the ECG shows peaked T waves and decreased amplitude of P waves followed by prolongation of QRS waves. With severe hyperkalemia, QRS and T waves blend together into what appears to be a sine-wave pattern consequent with ventricular fibrillation. Because cardiac arrest tin can occur at any point in this progression, hyperkalemia with ECG changes constitutes a medical emergency. Other effects of hyperkalemia include weakness, neuromuscular paralysis (without primal nervous arrangement disturbances), and suppression of renal ammoniagenesis, which may result in metabolic acidosis.
Chou TC: Electrolyte imbalance. In Chou TC, Knilans K (eds): Electrocardiography in Clinical Exercise, fourth ed. Philadelphia, WB Saunders, 1996, pp 532–535.
David B. Cadet , Geraldine A. Buck , in Physician Assistant (Fourth Edition), 2008
Electrocardiograms
Electrocardiography (ECG) is the report of the electrical conduction system of the centre. By applying surface electrodes to the patient's pare, one tin can obtain tracings of the electric activeness of the center for examination. The electrodes are divided into three reference systems: limb leads—leads I, Ii, and III; augmented leads—leads aVR, aVL, and aVF; and precordial leads—51 through 56. Correct placement of the 12 leads is critical for authentic ECG tracings to be obtained. Cardiac dysrhythmia, atrial and ventricular hypertrophy, myocardial ischemia and infarction, and axis deviation are but a few of the abnormalities found on ECG. Single-lead electrocardiographs, known as Holter monitors, may be worn around the clock past patients in whom infrequent dysrhythmias are suspected. Past using a Holter monitor to record heartbeats over extended periods, the dr. assistant may identify underlying disease not found on routine ECG. Postoperative cardiac patients also habiliment Holter monitors during the 3 to 5 days immediately after surgery for abiding monitoring of the cardiac rhythm to let rapid and early detection of deteriorating cardiac status. Patients requiring antiarrhythmic medications also may wear Holter monitors to enable evaluation of the efficacy of handling.
Electrocardiography is performed as part of the practise stress test, in which the patient is maximally exercised while continuous ECG tracings record the myocardial response to the demands of exercise; this provides identification of the presence or absence of coronary artery affliction. Some indications for ECG include a complaint of chest hurting, shortness of jiff, or other symptom suggestive of cardiopulmonary disease; preoperative screening; fettle screening; and the evaluation of hypertensive and diabetic patients who are at increased risk for cardiac disease.
a portable device used for 24 h that continuously records the patient's ECG during usual daily action.
Aberrant chronotropic response
inadequate increase in heart charge per unit during exercise testing.
Abnormal inotropic response
inadequate increase in systolic blood pressure during exercise testing.
Achalasia
an esophageal move disorder in which the smooth muscle layer of the esophagus loses normal peristalsis (muscular ability to motility nutrient downward the esophagus), and the lower esophageal sphincter fails to relax properly in response to swallowing.
Atrial fibrillation
an abnormality in the centre rhythm that involves irregular and often rapid beating of the heart and is related to thromboembolic phenomena.
Cardiac resynchronization (biventricular pacing)
a handling for heart failure that uses a three-lead biventricular pacemaker implanted in the breast. The pacemaker sends tiny electrical impulses to the heart muscle to coordinate (resynchronize) the pumping of the chambers of the heart, improving the heart's pumping efficiency. Both ventricles are paced to contract at the same fourth dimension. This tin reduce the symptoms of centre failure.
Complete atrioventricular block
too known as third-degree middle block, it is a rhythm disorder in which the impulse generated in the sinus node in the atrium does not propagate to the ventricles.
Couplets
two ectopic beats occurring one after the other.
Dyskesia (dyschezia)
difficulty in defecation.
Fecaloma
a tumor made of feces.
First-degree atrioventricular block
a disease of the electrical conduction system of the heart in which the PR interval is diffuse across 0.20 s.
Gallop rhythm
a usually abnormal rhythm of the heart on auscultation. Information technology includes three or 4 sounds, thus resembling the sounds of a gallop.
Intracardiac electrophysiological study
placement of multiple catheter electrodes into the heart for the diagnosis and management of selected cardiac weather. This process has been used mainly for identifying the mechanisms, site, and severity of brady- or tachyarrhythmias.
Low QRS voltage
voltage of entire QRS circuitous in all limb leads of the ECG <5 mm.
New York Heart Clan functional form
a functional classification of heart failure into four stages according to the type of activity causing shortness of breath: I (intense physical activity); II (moderate physical activity); 3 (mild physical activity); Iv (residual).
Nonsustained ventricular tachycardia
a catamenia of three or more than ventricular ectopic beats lasting less than 30 s.
Primary ST-T changes
ST-T wave changes that are independent of changes in ventricular activation and that may exist the result of global or segmental pathologic processes that touch on ventricular repolarization.
Programmed ventricular stimulation
a minimally invasive process which tests the electrical conduction system of the heart to appraise its electrical activity and conduction pathways.
Sinus node dysfunction
a grouping of aberrant centre rhythms presumably caused by a malfunction of the sinus node (the heart'due south master pacemaker).
Stokes-Adams syndrome
sudden plummet into unconsciousness due to a disorder of heart rhythm in which at that place is a slow or absent pulse resulting in syncope (fainting) with or without convulsions.
Transcatheter ablation
an invasive procedure used to remove a faulty electrical pathway responsible for some cardiac arrhythmias. Catheters are advanced toward the heart and high-frequency electrical impulses are used to induce the arrhythmia, and then ablate (destroy) the aberrant tissue that is causing it.
Volvulus
a bowel obstruction in which a loop of bowel has abnormally twisted on itself.
Xenodiagnosis
procedure allowing the feeding of laboratory-reared triatomine bugs (known to be infection-free) the blood of patients suspected of having Chagas disease; after several weeks, the bug feces are checked for the presence of Trypanosoma cruzi.
R.T. Rubin , B.J. Carroll , in Encyclopedia of Stress (Second Edition), 2007
Handling of Major Low and Manic-Depression
The offset outcome in the handling of patients with major depressive and bipolar disorder is to assess their immediate personal safety in light of the severity of their illness. For depressed patients, this always includes an assessment of their suicide potential. For manic patients, it includes not only an assessment of their suicide potential, peculiarly in mixed bipolar disorder, only also whether their behavior is harmful (due east.g., excessive booze intake, ownership sprees, sexual indiscretions, or foolish business decisions, as mentioned earlier). The most certain way to interrupt behavioral indiscretions and protect the individual from suicide attempts is hospitalization in a specialized psychiatric unit whose staff is trained in the care of such patients. If the patient resists hospitalization, an involuntary hold may exist medically and legally justified. A locked psychiatric unit of measurement, which prevents the patient from leaving, may be necessary until the illness is sufficiently under control that the patient's better judgment returns.
The treatment of major depression and bipolar disorder virtually always requires drug therapy with antidepressants and/or mood-stabilizing drugs. There are several chemic classes of antidepressant drugs, and they have specific pharmacological activities in the CNS. As previously mentioned, many of them cake the transporters for norepinephrine and/or serotonin, which recycle the neurotransmitters from the synapse back into the nerve cells that released them. By blocking transporter uptake, antidepressants increment synaptic neurotransmitter concentrations.
The time class for a total clinical response to antidepressant drugs is iii–6 weeks, even though their pharmacological furnishings occur within 12–24 h. Often, improved sleep may be an early sign of response to medication, specially with antidepressants that accept sedative side effects. Objective signs of improvement usually precede the patient's feeling better; for example, the person may be sleeping and eating improve, may accept more energy and a higher level of activities, and may be speaking more cheerfully, just he or she even so may be lament about feeling as depressed as before. The subjective depressed mood is often the last attribute of the affliction to ameliorate. Because the subjective experience of depression is so psychologically painful and stressful, information technology is very important that a patient with suicide potential not be released from the hospital until he or she is in sufficient behavioral control to no longer exist a suicide risk subsequently discharge.
As mentioned, some antidepressants are specific uptake inhibitors of norepinephrine and others of serotonin, but it is not possible to predict which depressed patient will reply to which antidepressant. This is most likely on the basis of the physiological interactions of neurotransmitter systems and, as previously indicated, the fact that near all antidepressants result in downregulation of postsynaptic noradrenergic receptors and induction of BDNF over the aforementioned fourth dimension course as clinical improvement occurs. Antidepressants therefore are usually called on the basis of their side effects and cost, those under patent being more expensive than those available in generic form. Many of the older antidepressants take prominent side effects, such as causing dry oral fissure, blurred vision, and especially changes in the electrical conduction arrangement of the heart. This last side event can exist particularly dangerous in accidental or deliberate drug overdose.
The class of antidepressant drugs currently in greatest use is the serotonin uptake inhibitors (SUIs). The commencement SUI accepted for clinical use in the United States was fluoxetine (Prozac). The SUIs may not exist quite as effective every bit the original tricyclic and monoamine oxidase inhibitor antidepressant drugs, particularly in severe low, but they take fewer side effects, especially cardiac, which makes them generally safer drugs to use. They do have other side effects that must be considered, including weight proceeds, decreased sexual drive, akathisia (inner restlessness), and some increased take chances of suicidal thinking or gestures. Although information technology has not been established that antidepressant drugs provoke completed suicides, regulatory warnings emphasize that patients must exist followed closely for this risk during the early weeks of handling.
Contempo studies have shown that the efficacy of the SUIs in the broad, heterogeneous group of patients diagnosed with major depression is pocket-size at all-time. The Number Needed to Care for (NNT) is a standard therapeutics measure out that denotes the number of patients who must receive a drug for one drug-attributable therapeutic result to be achieved, that is; over and to a higher place the placebo response rate. For the SUIs, the NNT ranges from 5 to twelve, whereas the NNT for the early tricyclic antidepressant drugs in severe, hospitalized depressed patients was iii. Contempo studies also ostend that there is no significant difference in response or remission rates between SUIs and some other newer antidepressants vs. placebo in mild low. The National Found for Clinical Excellence (NICE) in Britain therefore has recommended that nondrug treatments exist used first in mild depression.
A new class of antidepressant drugs that block synaptic reuptake of both norepinephrine and serotonin (e.g., venlafaxine and duloxetine) has recently appeared. The dual activeness of these drugs recapitulates the pharmacodynamic profile of original antidepressant agents such as imipramine, amitryptiline, and phenelzine, merely with a greatly reduced side-result profile. These dual-activeness drugs appear to be more effective than the SUIs in treating major depression. For instance, in direct comparisons, the NNT for venlafaxine to produce remission is 5, compared with ten for the SUIs.
The other major class of drugs used in mood disorders, especially in bipolar disorder, is the mood stabilizers. For manic patients, lithium is the almost effective. Lithium is a metal ion, in the same class in the periodic table of elements as sodium and potassium. Lithium has a number of effects on neurotransmission in the CNS. Information technology has a relatively narrow therapeutic alphabetize; that is, the claret concentrations at which lithium exerts toxicity are not very far above the concentrations required for its therapeutic effect. Therefore, patients taking lithium crave frequent measurement of their circulating lithium concentrations, specially at the outset of handling, to determine the daily dose necessary to achieve a therapeutic blood level. Lithium takes several weeks to achieve its full antimanic issue. It is a mood stabilizer rather than a pure antimanic compound, so bipolar patients who switch from mania into depression are usually continued on their lithium if an antidepressant is added.
For major depressive and bipolar patients, additional dimensions of their illnesses may advise the demand for other medications in addition to antidepressants and lithium. For example, prominent psychotic features in either illness may telephone call for an antipsychotic medication to be used concomitantly. For the treatment of depression, hormone supplements such as estrogens in women and thyroid hormone may be helpful. For the treatment of bipolar disorder, a number of anticonvulsant medications accept been shown to be effective, oft as augmentation of lithium treatment. Compounds such as carbamazepine, valproate, and lamotrigine are currently in use, and several newer anticonvulsants are being tested for their mood-stabilizing backdrop.
After the successful drug handling of a start lifetime episode of major low, continuation handling at full dosage is advised for 9 to 12 months to forestall relapse. The slow reduction of the medication then is attempted. Patients who feel recurrent depression, specially those who have had three or more than lifetime episodes, require long-term antidepressant maintenance handling at full dosage to prevent recurrences. Controlled trials have established that, even later iii years of successful preventive drug handling, 50% of such patients volition have a recurrence inside half dozen months of stopping their medication.
Bipolar patients need to accept medication adjustments fabricated according to the frequency of their manic and depressive mood swings; it may take years for the timing of these cycles to be clearly understood. Both disorders should exist viewed as chronic illnesses, ofttimes relapsing over a person's lifetime. If strenuous attempts at drug treatment of either disorder fail, ECT often will provide definitive relief of symptoms. Usually, 10 treatments are given, iii per week. The patient may suffer some memory loss during and following the treatments, just this is short-lived, whereas the therapeutic effect tin exist remarkable, specially in patients resistant to drug therapy. Unilateral, brief pulse awarding of electrical current to the nondominant hemisphere tin reduce these retentivity changes significantly. Maintenance ECT, oftentimes 1 treatment every calendar month or and so, tin be useful to continue the person in remission from his or her illness.
In add-on to pharmacotherapy and ECT, psychotherapies of different types, such every bit cognitive-behavioral therapy, oftentimes are useful to help the person change his or her lifestyle and manner of thinking well-nigh adversity. An improvement in self-esteem often results, which may protect confronting future episodes of depression or at to the lowest degree may reduce their severity.
Engineering science Niches for Cardiovascular Tissue Regeneration
Kay Maeda , ... Marc Ruel , in Biology and Engineering of Stem Cell Niches, 2017
4 Biomaterial Engineering for Cardiac Regeneration
Biomaterials tin be used as a jail cell-seeded tissue scaffold and/or as a carrier for the commitment of cellular material and/or signaling molecules in the center. Numerous studies have tested delivering stem cells with biomaterials as a solution to meliorate prison cell engraftment, survival, and proliferation after transplantation.3
There are two main sources of the biomaterial: natural and synthetic.32 Natural biomaterials used for scaffolds consist of ECM components, such equally collagen, fibrin, and even the whole decellularized natural ECM. These have the benefits of being bioactive and biocompatible, with mechanical properties potentially more closely matched to those of the native tissue. The main reward of natural biomaterials is their ability to interact with cells through adhesion molecules, thus providing native signaling necessary for proper prison cell office. Synthetic materials consist of classically singled-out materials, including metals, polymers, and ceramics. Their mechanical backdrop can exist made to exist superior to natural materials. Therefore, the advantages of synthetic materials are their strength, durability, and availability. These natural and constructed biomaterials can be used with cells and/or various signaling molecules to augment the intrinsic repair process and provide a suitable environment for the desired cells (host or transplanted).3,32
At present, there are three main approaches to tissue regeneration: (i) in situ injection of cells with or without a supporting matrix, into the damaged tissues33,34; (2) cell implantation within a preformed 3D scaffold generated past bioreactor systems35; and (3) the scaffold-based delivery of signaling molecules, depression-molecular-weight drugs, and oligonucleotides that support endogenous jail cell recruitment, migration, growth, and differentiation.36–39 In the following sections, we provide an overview of biomaterials equally stem cell niches and their application in cardiac regeneration. Fig. 29.2 provides a simplified view of biomaterial-based strategies for introducing regenerative cells and approaches of administrating tissue engineered constructs.
Cells, scaffolds, and signaling molecules tin can be introduced alone or in combination at the injury site. Scaffolds provide biophysical, topographical, and biochemical microenvironments to the transplanted and host cells. Mechanical stiffness of biomaterials can guide proper stem prison cell differentiation. Stretch is a typical function of the cardiovascular system and has been shown to guide differentiation of stem cells toward cardiomyocytes or smooth muscle cells. Nanotopography of the biomaterial tin affect stem prison cell phenotype, cellular alignment, and electrophysical backdrop.
iv.1 Biomaterials as Stem Prison cell Niches
Stem cells are stored in niches throughout the body. Inside the heart, the niches control the physiological turnover of cardiac cells and the migration and proliferation of cardiac stalk cells to replace damaged cells in the myocardium.25 The cardiac ECM tin can promote stem prison cell differentiation toward the CM lineage.25 Thus ECM-based biomaterials, derived from human or animal tissue, may serve every bit an appropriate scaffold for the generation of newly developed tissues. The almost direct approach to mimic the native environment is to use the myocardial ECM itself. Decellularization is a process whereby living cells and nuclear material are removed from tissues without affecting the structural integrity and desired composition of the ECM.40,41 Due to the high conservation of ECM elements, the decellularized ECM scaffolds tin can be integrated or incorporated into the trunk and provide cell- or tissue-specific support. Ott et al. have demonstrated whole heart engineering past decellularizing hearts using a detergent extraction method, retaining the underlying ECM and vascular architecture with intact chambers.xl When cardiac-derived cells and ECs were reseeded into the decellularized heart, these cells could self-assemble, reorganize, and produce contractile responses when electrically stimulated (Fig. 29.3). Whole heart engineering yet requires optimization for clinical applications, but it has the potential to transplant new functional autologous hearts in part or as an entire donor organ for patients who need a transplant. Another approach is to utilise decellularized cardiac ECM to generate an injectable cardiac ECM hydrogel. Singelyn et al. accept developed decellularized porcine myocardial ECM every bit an injectable scaffold that can retain components of the natural cardiac ECM.41 In both in vitro and in vivo experiments, this decellularized myocardial matrix increased neovascularization and the recruitment of endogenous ECs and SMCs into the infarct area, resulting in preserved cardiac function. Such a cardiac ECM has been shown to be safe and effective in a clinically relevant porcine MI model.42
Figure 29.three. Decellularized whole adult rat hearts could incorporate instructive signals for cardiac role.
(A) Macroscopic view of coronary corrosion casts of cadaveric and decellularized rat hearts shows that decellularization could retain underlying extracellular matrix and vascular compages with intact chambers. (B) Recellularized heart with a mixed population cardiomyocytes, fibroblasts, endothelial cells, and smooth musculus cells, takes on functional properties in a thing of days when electrically stimulated. (Left) Representative functional assessment tracing of decellularized whole heart construct paced in a working eye bioreactor preparation at twenty-four hour period 0. Real-time tracings of ECG, aortic pressure (afterload), and left ventricular force per unit area (LVP) are shown. (Center) Images of recellularized hearts on civilization 24-hour interval 4 with pump turned off. Existent-fourth dimension tracings of a region of movement are shown below each image in blue, green, and cherry. (Right) Tracing of ECG, aortic pressure level (afterload), and LVP of the paced construct are shown on 8 days afterward recellularization and on 24-hour interval 8 afterwards stimulation with physiological (l–100 M) doses of phenylephrine.
From Ott HC, Matthiesen TS, Goh SK, Black LD, Kren SM, Netoff TI, et al. Perfusion-decellularized matrix: using nature'due south platform to engineer a bioartificial heart. Nat Med 2008;fourteen(2):213–21.
Biomaterials cannot only provide a naturally occurring extracellular environment simply can also control the biochemical microenvironment of transplanted stem cells and raise stem jail cell office. For instance, an ECM scaffold derived from porcine small abdominal submucosa (SIS-ECM) has been one of the most extensively characterized decellularized ECM materials. Sister-ECM scaffold is frequently cited as a prototypical ECM scaffold, and it could provide an ideal extracellular surroundings for cardiac cells because of its high content of cardiac ECM elements, such as collagen types I, Three, IV, V, and Vii, fibronectin, elastin, glycosaminoglycans, glycoproteins, and diverse GFs. Injectable decellularized Sister-ECM was shown to promote cellular infiltration (c-kit+ cells, myofibroblasts, and macrophages) and ameliorate cardiac function in an MI rat model.43 It has been demonstrated that a SIS-ECM textile seeded with stem cells is successful in treating MI. In a rabbit MI model, MSC-seeded SIS-ECM patches significantly improved LV contractile function and dimensions and the capillary density of the infarcted area.44 MSCs migrated into the infarcted area and differentiated to CMs and SMCs in the SIS-ECM treated groups. Sister-ECM treatment may accept enhanced local cardiomyogenesis and express the extent of adverse LV remodeling. The damaged tissue forms a barrier that disrupts the electric conduction organization of the eye, resulting in an arrhythmia, including ventricular tachycardia and AF. In a retrospective clinical report on patients undergoing primary isolated coronary artery bypass grafting, pericardial reconstruction with Sister-ECM for pericardial closure contributed to a statistically meaning decrease in the charge per unit of postoperative AF,45 showing enhanced electrical signal transmission between cells via the material. Overall, these studies demonstrate that a naturally derived decellularized ECM has the potential in the nigh future for clinical use every bit a scaffold therapy with or without stem cells.
four.2 Biomaterial Properties in Cardiovascular Regenerative Therapy
An platonic biomaterial should meet various required backdrop for application in humans. 1 indispensable belongings is biocompatibility, such that information technology is biodegradable with deposition products that are nontoxic and non-immunogenic. The following backdrop are also essential for clinical apply: biocompatible mechanical properties (eastward.g., supporting cell construct, resistant to stress/strain), ability to exist sterilized, and biomechanical characteristics like to those of the tissue it is replacing.46,47
During the last 5 years, understanding in the field of electrically conductive scaffolds for heart tissue regeneration has brought promising attempts to produce more functional cardiac patches. The native myocardium has an organized conduction arrangement facilitated by fast-signing bundles and Purkinje fibers.48,49 About scaffolds used in cardiac tissue applied science are electrically insulating. Novel biomaterials take recently been developed to improve cardiac electrical indicate propagation and cell alignment (Fig. 29.iv).48,50 You et al. have adult microporous constructed polymeric scaffolds with immobilized gold nanoparticles, resulting in an increase in the expression of connexin43, known to exist gap-junction proteins, in embryonic rat CMs.48 Dvir et al. have created alginate hydrogels with incorporation of gold nanowires in the macroporous walls.fifty Gilt nanowires deed as conductive bridges, resulting in improved CM electrophysiological and contractile behavior. A like concept was afterward employed for the development of macroporous nanowire nanoelectronic scaffolds for sensing various microenvironmental atmospheric condition.51 Cells integrated with these nanohybrid scaffolds could allow spatiotemporal electrical signal propagation, and exhibited a morphology resembling those found in a natural heart tissue.
Effigy 29.4. Engineering of electrically conductive scaffolds.
(A) Gold nanowires act equally conductive bridges when embedded in macroporous alginate hydrogels to allow better electric point propagation and contractile behavior of cardiomyocytes. (B) Nanoelectronics integrated into cardiac tissue allows spatiotemporal electrical indicate propagation. (C) Methacrylated gelatin hydrogel sheets containing carbon nanotubes influence cardiomyocyte jail cell alignment and mechanical properties.
(A) From Dvir T, Timko BP, Brigham MD, Naik SR, Karajanagi SS, Levy O, et al. Nanowired three-dimensional cardiac patches. Nat Nanotechnol 2011;6(11):720–25. (B) From Tian B, Liu J, Dvir T, Jin L, Tsui JH, Qing Q, et al. Macroporous nanowire nanoelectronic scaffolds for synthetic tissues. Nat Mater 2012;xi(11):986–94. (C) From Shin SR, Jung SM, Zalabany Grand, Kim K, Zorlutuna P, Kim South, et al. Carbon-nanotube-embedded hydrogel sheets for applied science cardiac constructs and bioactuators. ACS Nano 2013;7(3):2369–80.
Gelatin hydrogel containing carbon nanotubes improved the adherence of CMs, their actinic and troponin expression, and their mechanical properties.49 Mooney et al. have reported that MSCs could exist stimulated and induced to differentiate into CMs on a polylactic acrid scaffold embedded with carbon nanotubes.52 The improver of carbon nanotubes creates a nanofibrous construction that closely mimics the size scale of intrinsic ECM.49
Topological properties act together with ecology induction signals under different conditions to regulate cell behavior. Heidi et al. take adult a microfabricated system incorporating biphasic electrical pulses and topographical cues on cell culture chips.53 The fries were hot embossed into polystyrene surrounded past gold electrodes to create microgrooves and microridges of exactly defined depth, width, and ridge. Topography had a greater influence on CMs' phenotype and cellular alignment. The cultivation of CMs on nanogrooves patterned on poly(ethylene glycol) (PEG) hydrogels resulted in a significantly functional increment in prison cell alignment, Cx43 expression, and conduction velocity.54 Chiu et al. have demonstrated that CMs cultured on photocrosslinkable collagen-chitosan hydrogels with microgrooves significantly improved electrophysical backdrop compared with smooth hydrogels, with the smaller groove producing the best results for prison cell elongation and orientation.55 The topographical roughness of scaffold surfaces has proved to heighten the cell attachment and proliferation.
four.three Scaffolds for Codelivery With Growth Factors
One of the limitations to the scaffold-based approach for the delivery of cells is the potential deficiency of oxygen, diet, and signals supplied to the cells within the scaffold matrix. However, biomaterials tin too be used to evangelize proteins, genes, or minor RNAs together with therapeutic cells, and such a codelivery strategy may overcome these inadequacies.32,39
In ane of the first investigations of the codelivery of cells and GFs within a scaffold for myocardial tissue repair, IGF-1 was tethered to cocky-assembling peptide nanofibers (NF-IGF-1), leading to prolonged IGF-ane release into the myocardium and improved cardiac part of neonatal CMs in a rat MI model compared with that of cell-seeded NF without GFs and GFs alone.56 In some other study, NF-IGF-1 local injection forth with cardiac progenitor cells (CPCs) was shown to enhance the differentiation of resident and delivered CPCs into mature CMs, resulting in improved cardiac part in a rat MI model, compared with CPCs and to NF-IGF-i lonely.57 Self-assembling peptide nanofibers with SDF-ane, known to be a chemotactic protein for EPCs, led to enhanced EPC homing, increased capillary density and improved cardiac function.nineteen
Codelivery of stem cells with GFs has been shown to raise angiogenesis and vasculogenesis in vitro and in vivo.13 Silva et al. accept shown that an injection of vasculogenic progenitor cells, delivered from macroporous alginate scaffolds that release VEGF, improved engraftment of delivered cells in ischemic murine hind limb musculature, increased blood vessel densities, and further improved limb perfusion compared with stand-alone delivery.31 Introducing EPCs inside scaffolds and GF-recruited circulating EPCs increased the local EPCs, which contributed to enhanced vascularization.58 Our group has developed encapsulated SDF-1 release system in ischemic hind limb mice models.59 Injectable collagen matrix integrated with SDF-1-encapsulating alginate microspheres stimulated endogenous stalk jail cell-mediated regenerative responses and neovascularization in the ischemic hind limb of mice.
Codelivery of cells and GFs within scaffolds could maximize their effectiveness for functional tissue regeneration. Ultimately, many approaches will likely crave organization of molecularly designed biomaterials with stalk cells to develop stable tissue regeneration.
Long-term outlook for transcatheter aortic valve replacement
Andras P. Durko MD , ... A. Pieter Kappetein Medico, PhD , in Trends in Cardiovascular Medicine, 2018
Permanent pacemaker need later on TAVR
Due to the proximity of the electrical conduction system of the heart to the aortic annulus, rhythm disturbances tin occur after aortic valve replacement, ofttimes necessitating permanent pacemaker implantation. Permanent pacemaker demand after SAVR was effectually 5% in a big US database, while it is around x% following TAVR according to the TVT registry written report [33,34]. Balloon-expandable designs are associated with lower pacemaker rates when compared to self-expandable ones [eighteen,nineteen]. In a recently developed model, pre-procedural correct bundle branch block, shorter bleary septum and noncoronary cusp device-landing zone calcium book were identified every bit predictors of pacemaker demand afterward TAVR with a tertiary-generation balloon-expandable prosthesis [35]. Of note, pacemaker requirement after TAVR too varies between different valve generations, and is influenced by the technique of implantation [36].
Robert Roberts MD FACC , in Journal of the American College of Cardiology, 2006
Future of genomics in cardiovascular arrhythmias
While cardiac arrhythmias may be associated with or without structural heart disease, the defect always involves some aspect of the electric conduction system of the heart. The structural component is, of course, the sinus node, specialized atrial tracts, atrioventricular node, and package of HIS with the Purkinje system. After conducting within this specialized electrical transmission, the current must laissez passer into other cells such as myocytes. The important components are predominantly ionic currents, ion channels, structural proteins, and gap junctions. Most of the genetic defects currently identified involve some aspect of the subunits of the ion channels. We at present recognize at least 429 genes that encode ion channel proteins in the human (79). Of these, 170 encode potassium channels, 38 are for calcium channels, 29 are for sodium channels, 58 are for chloride channels, and 15 are glutemate receptors (80). It is of interest that ion channels represent only nearly five% of the molecular targets of modernistic medicine (81,82). It is now recognized that in addition to the role of ion channels regulating membrane potential they also regulate many other functions including cell book and hormone secretion (83,84). The complexity of these channels, such as the voltage-gated cardiac potassium channels, is such that several domains exist within the integrated channel protein. In addition to the pore domain, there are the domains that provide ion selectivity, opening and endmost of the gate together with the sensing units whether it exist voltage or chemic. The elucidation of mutations causing disease is rapidly enhancing our understanding of the topography and sequences involved with each domain. Approaches past the pharmaceutical industry to develop designer drugs for those domains, while in its infancy, are rapidly developing.
The feature characteristic of the electric activity of the center is the AP of the atria and ventricles due to depolarization and repolarization with the feature long plateau phase involving multiple ion channels. Many of these channels have now been cloned and will serve as prime number candidates for the identification of genetic defects in the future. The major currents involved in the atrial and ventricular AP are indicated in Effigy two. Cardiac electrical activity is thus a complex process, which integrates the electrical action of multiple molecules. Any variant in either of these molecules whether information technology is due to SNPs or greater defects can significantly alter cardiac activeness. It is well recognized that structural heart affliction, associated with either hypertrophy or cardiac dilatation, can structurally affect electrical transmission or through altered gene expression induce arrhythmias. Hypertrophy is well documented to increment the propensity for SCD by well-nigh 4-fold. Structural heart disease is associated with excessive fibrous tissue, which has a lower velocity of conduction and could pb to re-entry arrhythmias. Mutual genetic variants accept been shown to increase the risk of cardiac arrhythmias, and nearly recent studies prove that fifty-fifty mutual genetic variant in genes referred to as SNPs can change cardiac electric manifestations in certain populations. Atrial fibrillation is associated with pregnant morbidity in the aging population. Ventricular fibrillation is a lethal arrhythmia responsible for over 600,000 deaths each year in the Western world. Both atrial and ventricular fibrillation remain the most challenging of rhythm disorders.
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