Which of the following is responsible for sending out electrical impulses that spread over muscles in the atria and is known as the pacemaker?

Impulse Conduction

The specialized electrical conduction system of the heart allows for the synchronous contraction of the left and right sides of the heart and the sequential contraction of the atria and ventricles (Figure 1(b)). Electrical impulses most quickly arise in the spontaneously firing cells of the sinoatrial (SA) node commonly 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 right atrium, then to the cells of both atria, finally converging on a second 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 two 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 muscle.

If a microelectrode is inserted into a resting muscle or nerve cell (termed ‘excitable tissue’), an electrical potential difference will be recorded across the membrane of that cell. In the case of cardiac muscle cells, this resting potential is −90 mV (intracellular relative to extracellular). In other words, the cell membrane is electrically polarized with the inward 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 muscle cell, the concentration of potassium ions (K+) is higher inside the cell than outside, while sodium ions (Na+) are at a much higher concentration outside the cell than inside. Cellular energy is required to maintain the appropriate resting state distributions of the different ions across the cell membrane. In the case of K+ and Na+ ions, there is a cell membrane pump, which requires energy derived from the hydrolysis of the terminal phosphate group from adenosine triphosphate (ATP). The associated enzyme responsible for this hydrolysis is the Na+–K+ ATPase. When an electrical stimulus is received by a cardiac muscle cell, voltage-gated channels in the cell membrane open allowing Na+ to diffuse down its concentration and electrical gradients into the cell. This influx of positive charge causes the cell membrane to become ‘depolarized’ (i.e., to have less negative charge). As depolarization proceeds, the membrane may reach the threshold potential (−70 mV for most cardiac muscle cells). Any further depolarization results in a phenomenon known as the action potential, which completely depolarizes the cell. At the peak of the action potential, the inside of the cell actually becomes positive relative to the outside (+30 mV). The cell membrane then repolarizes relatively slowly and reaches the −90 mV resting potential before it can respond to another electrical impulse. The wave of depolarization moves very rapidly across the membrane of an individual cardiac muscle 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 contraction of the heart muscle as a group.

Cardiac muscle cells predominantly display a fast response action potential (Figure 2), 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 five phases. Phase 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 phase 0, the cell is completely depolarized. Toward the end of phase 1 and the start of phase 2, 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 only takes place after the membrane potential has dropped to approximately −55 mV, that is, after the ‘fast’ Na+ ion current has ceased. While these ‘slow’ inward currents occur, there is also a slow outward movement 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 past the thin actin filaments in the contractile unit of the muscle known as the sarcomere. This process requires 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 amount of Ca2+ ions that reaches the site of contraction. Within the resting muscle cell, Ca2+ is sequestered in a compartment called the sarcoplasmic reticulum. During the action potential, Ca2+ and Na+ ions that enter the cell cause depolarization of the sarcoplasmic reticulum membrane, resulting in the release of large amounts of Ca2+, which are needed for effective contraction of the sarcomere. Between contractions, Ca2+ is once again sequestered in the sarcoplasmic reticulum so that the actin–myosin interaction is not overly prolonged. During the long duration of the plateau phase, a new action potential cannot be initiated because the ‘fast’ Na+ channels are inactivated or refractory to further electrical stimulation. During phase 3, membrane permeability to K+ increases and the ‘slow’ Ca2+ and Na+ channels become inactive. The ensuing efflux of K+ ions allows for repolarization of the membrane until the normal resting potential is reached (phase 4).

In contrast, conduction velocity is slow in muscle fibers at the SA and AV nodes. Unlike the majority of cardiac muscle cells, these pacemaker cells have 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 K+ ion efflux. This Na+ leakage reduces the membrane potential allowing even more Na+ ions to move into the cell. In addition to the inward Na+ movement, there is also an inward Ca2+ flow which causes the pacemaker cells to have a more positive resting potential. Finally, the 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. As noted previously, this phenomenon occurs ∼72 times per minute (more or less depending on autonomic nervous system stimulation, periods of stress, or physical activity). The SA node is responsible for this rate as it depolarizes the fastest. The other nodes and components of the cardiac conduction may also drive depolarizations, only slowly. The purpose of this redundancy is to ensure pacemaker activity in the heart (to support cardiac homeostasis). The waves of electrical activity may be recorded in an electrocardiogram (ECG), which displays the net electrical changes relative to where the recording electrodes are placed on the surface of the body.

Electrophysiologic Studies

EPSs are performed to evaluate the electrical conduction system of the heart.12 An electrode catheter is inserted through the femoral vein into the right ventricle apex. Continuous ECG monitoring is performed internally and externally. The electrode can deliver 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 about each segment of the conduction system.12 In many hospitals, these studies may be combined with a therapeutic procedure, such as an ablation procedure (discussed in the Management section). 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.

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 system of the heart. Profound hyperkalemia can lead 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 consistent with ventricular fibrillation. A good way to think about ECG changes in hyperkalemia is to imagine lifting the T wave, in which the T gets taller first followed by flattening of P and QRS. Other effects of hyperkalemia include weakness, neuromuscular paralysis (without central nervous system disturbances), and suppression of renal ammoniagenesis, which may result in metabolic acidosis.

15 What are the clinical manifestations of hyperkalemia?

The most serious manifestation of hyperkalemia involves the electrical conduction system of the heart. Profound hyperkalemia can lead 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 consistent with ventricular fibrillation. Because cardiac arrest 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 central nervous system 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 Practice, 4th ed. Philadelphia, WB Saunders, 1996, pp 532–535.

Electrocardiograms

Electrocardiography (ECG) is the study of the electrical conduction system of the heart. By applying surface electrodes to the patient's skin, one can obtain tracings of the electrical activity of the heart 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—V1 through V6. Correct placement of the 12 leads is critical for accurate 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 by patients in whom infrequent dysrhythmias are suspected. By using a Holter monitor to record heartbeats over extended periods, the physician assistant may identify underlying disease not found on routine ECG. Postoperative cardiac patients also wear Holter monitors during the 3 to 5 days immediately after surgery for constant monitoring of the cardiac rhythm to allow rapid and early detection of deteriorating cardiac status. Patients requiring antiarrhythmic medications also may wear Holter monitors to enable evaluation of the efficacy of treatment.

Electrocardiography is performed as part of the exercise 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 disease. Some indications for ECG include a complaint of chest pain, shortness of breath, or other symptom suggestive of cardiopulmonary disease; preoperative screening; fitness screening; and the evaluation of hypertensive and diabetic patients who are at increased risk for cardiac disease.

Glossary

24-h Holter monitoring (ambulatory Holter monitoring)

a portable device used for 24 h that continuously records the patient's ECG during usual daily activity.

inadequate increase in heart rate during exercise testing.

inadequate increase in systolic blood pressure during exercise testing.

an esophageal motility disorder in which the smooth muscle layer of the esophagus loses normal peristalsis (muscular ability to move food down the esophagus), and the lower esophageal sphincter fails to relax properly in response to swallowing.

an abnormality in the heart rhythm that involves irregular and often rapid beating of the heart and is related to thromboembolic phenomena.

a treatment for heart failure that uses a three-lead biventricular pacemaker implanted in the chest. 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 time. This can reduce the symptoms of heart failure.

also known as third-degree heart block, it is a rhythm disorder in which the impulse generated in the sinus node in the atrium does not propagate to the ventricles.

two ectopic beats occurring one after the other.

difficulty in defecation.

a tumor made of feces.

a disease of the electrical conduction system of the heart in which the PR interval is lengthened beyond 0.20 s.

a usually abnormal rhythm of the heart on auscultation. It includes three or four sounds, thus resembling the sounds of a gallop.

placement of multiple catheter electrodes into the heart for the diagnosis and management of selected cardiac conditions. This procedure has been used mainly for identifying the mechanisms, site, and severity of brady- or tachyarrhythmias.

voltage of entire QRS complex in all limb leads of the ECG <5 mm.

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); III (mild physical activity); IV (rest).

a period of three or more ventricular ectopic beats lasting less than 30 s.

ST-T wave changes that are independent of changes in ventricular activation and that may be the result of global or segmental pathologic processes that affect ventricular repolarization.

a minimally invasive procedure which tests the electrical conduction system of the heart to assess its electrical activity and conduction pathways.

a group of abnormal heart rhythms presumably caused by a malfunction of the sinus node (the heart's primary pacemaker).

sudden collapse into unconsciousness due to a disorder of heart rhythm in which there is a slow or absent pulse resulting in syncope (fainting) with or without convulsions.

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 abnormal tissue that is causing it.

a bowel obstruction in which a loop of bowel has abnormally twisted on itself.

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.

Treatment of Major Depression and Manic-Depression

The first issue in the treatment 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, especially in mixed bipolar disorder, but also whether their behavior is harmful (e.g., excessive alcohol intake, buying 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 be medically and legally justified. A locked psychiatric unit, 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 almost always requires drug therapy with antidepressants and/or mood-stabilizing drugs. There are several chemical classes of antidepressant drugs, and they have specific pharmacological activities in the CNS. As previously mentioned, many of them block 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 increase synaptic neurotransmitter concentrations.

The time course for a full clinical response to antidepressant drugs is 3–6 weeks, even though their pharmacological effects occur within 12–24 h. Often, improved sleep may be an early sign of response to medication, especially with antidepressants that have sedative side effects. Objective signs of improvement usually precede the patient's feeling better; for example, the person may be sleeping and eating better, may have more energy and a higher level of activities, and may be speaking more cheerfully, but he or she still may be complaining about feeling as depressed as before. The subjective depressed mood is often the last aspect of the illness to improve. Because the subjective experience of depression is so psychologically painful and stressful, it 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 be a suicide risk after 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 respond to which antidepressant. This is most likely on the basis of the physiological interactions of neurotransmitter systems and, as previously indicated, the fact that almost all antidepressants result in downregulation of postsynaptic noradrenergic receptors and induction of BDNF over the same time course as clinical improvement occurs. Antidepressants therefore are usually chosen 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 have prominent side effects, such as causing dry mouth, blurred vision, and especially changes in the electrical conduction system of the heart. This last side effect can be particularly dangerous in accidental or deliberate drug overdose.

The class of antidepressant drugs currently in greatest use is the serotonin uptake inhibitors (SUIs). The first SUI accepted for clinical use in the United States was fluoxetine (Prozac). The SUIs may not be quite as effective as the original tricyclic and monoamine oxidase inhibitor antidepressant drugs, especially in severe depression, but they have 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 gain, decreased sexual drive, akathisia (inner restlessness), and some increased risk of suicidal thinking or gestures. Although it has not been established that antidepressant drugs provoke completed suicides, regulatory warnings emphasize that patients must be followed closely for this risk during the early weeks of treatment.

Recent studies have shown that the efficacy of the SUIs in the broad, heterogeneous group of patients diagnosed with major depression is modest at best. The Number Needed to Treat (NNT) is a standard therapeutics measure that denotes the number of patients who must receive a drug for one drug-attributable therapeutic outcome to be achieved, that is; over and above the placebo response rate. For the SUIs, the NNT ranges from five to twelve, whereas the NNT for the early tricyclic antidepressant drugs in severe, hospitalized depressed patients was three. Recent studies also confirm that there is no significant difference in response or remission rates between SUIs and some other newer antidepressants vs. placebo in mild depression. The National Institute for Clinical Excellence (NICE) in Britain therefore has recommended that nondrug treatments be 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 action of these drugs recapitulates the pharmacodynamic profile of original antidepressant agents such as imipramine, amitryptiline, and phenelzine, but with a greatly reduced side-effect profile. These dual-action drugs appear to be more effective than the SUIs in treating major depression. For example, in direct comparisons, the NNT for venlafaxine to produce remission is five, 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 most 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. It has a relatively narrow therapeutic index; that is, the blood concentrations at which lithium exerts toxicity are not very far above the concentrations required for its therapeutic effect. Therefore, patients taking lithium require frequent measurement of their circulating lithium concentrations, especially at the outset of treatment, to determine the daily dose necessary to achieve a therapeutic blood level. Lithium takes several weeks to achieve its full antimanic effect. 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 suggest the need for other medications in addition to antidepressants and lithium. For example, prominent psychotic features in either illness may 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 have been shown to be effective, often 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 properties.

After the successful drug treatment of a first lifetime episode of major depression, continuation treatment at full dosage is advised for 9 to 12 months to prevent relapse. The slow reduction of the medication then is attempted. Patients who experience recurrent depression, particularly those who have had three or more lifetime episodes, require long-term antidepressant maintenance treatment at full dosage to prevent recurrences. Controlled trials have established that, even after 3 years of successful preventive drug treatment, 50% of such patients will have a recurrence within 6 months of stopping their medication.

Bipolar patients need to have medication adjustments made 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 be viewed as chronic illnesses, often 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, three per week. The patient may suffer some memory loss during and following the treatments, but this is short-lived, whereas the therapeutic effect can be remarkable, especially in patients resistant to drug therapy. Unilateral, brief pulse application of electrical current to the nondominant hemisphere can reduce these memory changes significantly. Maintenance ECT, often one treatment every month or so, can be useful to keep the person in remission from his or her illness.

In addition to pharmacotherapy and ECT, psychotherapies of different types, such as cognitive-behavioral therapy, often are useful to help the person change his or her lifestyle and manner of thinking about adversity. An improvement in self-esteem often results, which may protect against future episodes of depression or at least may reduce their severity.

4 Biomaterial Engineering for Cardiac Regeneration

Biomaterials can be used as a cell-seeded tissue scaffold and/or as a carrier for the delivery of cellular material and/or signaling molecules in the heart. Numerous studies have tested delivering stem cells with biomaterials as a solution to improve 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 as 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 primary advantage of natural biomaterials is their ability to interact with cells through adhesion molecules, thus providing native signaling necessary for proper cell function. Synthetic materials consist of classically distinct materials, including metals, polymers, and ceramics. Their mechanical properties can be made to be superior to natural materials. Therefore, the advantages of synthetic materials are their strength, durability, and availability. These natural and synthetic 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: (1) 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 by bioreactor systems35; and (3) the scaffold-based delivery of signaling molecules, low-molecular-weight drugs, and oligonucleotides that support endogenous cell recruitment, migration, growth, and differentiation.36–39 In the following sections, we provide an overview of biomaterials as 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.

4.1 Biomaterials as Stem Cell Niches

Stem cells are stored in niches throughout the body. Within the heart, the niches control the physiological turnover of cardiac cells and the migration and proliferation of cardiac stem cells to replace damaged cells in the myocardium.25 The cardiac ECM can promote stem cell differentiation toward the CM lineage.25 Thus ECM-based biomaterials, derived from human or animal tissue, may serve as an appropriate scaffold for the generation of newly developed tissues. The most 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 can be integrated or incorporated into the body and provide cell- or tissue-specific support. Ott et al. have demonstrated whole heart engineering by decellularizing hearts using a detergent extraction method, retaining the underlying ECM and vascular architecture with intact chambers.40 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 still 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 use decellularized cardiac ECM to generate an injectable cardiac ECM hydrogel. Singelyn et al. have developed decellularized porcine myocardial ECM as 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 29.3. Decellularized whole adult rat hearts could contain instructive signals for cardiac function.

(A) Macroscopic view of coronary corrosion casts of cadaveric and decellularized rat hearts shows that decellularization could retain underlying extracellular matrix and vascular architecture with intact chambers. (B) Recellularized heart with a mixed population cardiomyocytes, fibroblasts, endothelial cells, and smooth muscle cells, takes on functional properties in a matter of days when electrically stimulated. (Left) Representative functional assessment tracing of decellularized whole heart construct paced in a working heart bioreactor preparation at day 0. Real-time tracings of ECG, aortic pressure (afterload), and left ventricular pressure (LVP) are shown. (Center) Images of recellularized hearts on culture day 4 with pump turned off. Real-time tracings of a region of movement are shown below each image in blue, green, and red. (Right) Tracing of ECG, aortic pressure (afterload), and LVP of the paced construct are shown on 8 days after recellularization and on day 8 after stimulation with physiological (50–100 M) doses of phenylephrine.

From Ott HC, Matthiesen TS, Goh SK, Black LD, Kren SM, Netoff TI, et al. Perfusion-decellularized matrix: using nature's platform to engineer a bioartificial heart. Nat Med 2008;14(2):213–21.

Biomaterials cannot only provide a naturally occurring extracellular environment but can also control the biochemical microenvironment of transplanted stem cells and enhance stem cell function. For example, an ECM scaffold derived from porcine small intestinal submucosa (SIS-ECM) has been one of the most extensively characterized decellularized ECM materials. SIS-ECM scaffold is often cited as a prototypical ECM scaffold, and it could provide an ideal extracellular environment for cardiac cells because of its high content of cardiac ECM elements, such as collagen types I, III, IV, V, and VII, fibronectin, elastin, glycosaminoglycans, glycoproteins, and various GFs. Injectable decellularized SIS-ECM was shown to promote cellular infiltration (c-kit+ cells, myofibroblasts, and macrophages) and improve cardiac function in an MI rat model.43 It has been demonstrated that a SIS-ECM material 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. SIS-ECM treatment may have enhanced local cardiomyogenesis and limited the extent of adverse LV remodeling. The damaged tissue forms a barrier that disrupts the electrical conduction system of the heart, resulting in an arrhythmia, including ventricular tachycardia and AF. In a retrospective clinical study on patients undergoing primary isolated coronary artery bypass grafting, pericardial reconstruction with SIS-ECM for pericardial closure contributed to a statistically significant decrease in the rate 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 near future for clinical use as a scaffold therapy with or without stem cells.

4.2 Biomaterial Properties in Cardiovascular Regenerative Therapy

An ideal biomaterial should meet various required properties for application in humans. One indispensable property is biocompatibility, such that it is biodegradable with degradation products that are nontoxic and non-immunogenic. The following properties are also essential for clinical use: biocompatible mechanical properties (e.g., supporting cell construct, resistant to stress/strain), ability to be sterilized, and biomechanical characteristics similar 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 system facilitated by fast-signing bundles and Purkinje fibers.48,49 Most scaffolds used in cardiac tissue engineering are electrically insulating. Novel biomaterials have recently been developed to improve cardiac electrical signal propagation and cell alignment (Fig. 29.4).48,50 You et al. have developed microporous synthetic polymeric scaffolds with immobilized gold nanoparticles, resulting in an increment in the expression of connexin43, known to be gap-junction proteins, in embryonic rat CMs.48 Dvir et al. have created alginate hydrogels with incorporation of gold nanowires in the macroporous walls.50 Gold nanowires act as conductive bridges, resulting in improved CM electrophysiological and contractile behavior. A similar concept was later employed for the development of macroporous nanowire nanoelectronic scaffolds for sensing various microenvironmental conditions.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.

Figure 29.4. Engineering of electrically conductive scaffolds.

(A) Gold nanowires act as conductive bridges when embedded in macroporous alginate hydrogels to allow better electrical signal propagation and contractile behavior of cardiomyocytes. (B) Nanoelectronics integrated into cardiac tissue allows spatiotemporal electrical signal propagation. (C) Methacrylated gelatin hydrogel sheets containing carbon nanotubes influence cardiomyocyte 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;11(11):986–94. (C) From Shin SR, Jung SM, Zalabany M, Kim K, Zorlutuna P, Kim S, et al. Carbon-nanotube-embedded hydrogel sheets for engineering 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 be stimulated and induced to differentiate into CMs on a polylactic acid scaffold embedded with carbon nanotubes.52 The addition of carbon nanotubes creates a nanofibrous structure that closely mimics the size scale of intrinsic ECM.49

Topological properties act together with environmental induction signals under different conditions to regulate cell behavior. Heidi et al. have developed a microfabricated system incorporating biphasic electrical pulses and topographical cues on cell culture chips.53 The chips were hot embossed into polystyrene surrounded by 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 increase in 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 properties compared with smooth hydrogels, with the smaller groove producing the best results for cell elongation and orientation.55 The topographical roughness of scaffold surfaces has proved to enhance the cell attachment and proliferation.

Permanent pacemaker need after TAVR

Due to the proximity of the electrical conduction system of the heart to the aortic annulus, rhythm disturbances can occur after aortic valve replacement, often necessitating permanent pacemaker implantation. Permanent pacemaker need after SAVR was around 5% in a large US database, while it is around 10% following TAVR according to the TVT registry report [33,34]. Balloon-expandable designs are associated with lower pacemaker rates when compared to self-expandable ones [18,19]. In a recently developed model, pre-procedural right bundle branch block, shorter membranous septum and noncoronary cusp device-landing zone calcium volume were identified as predictors of pacemaker need after TAVR with a third-generation balloon-expandable prosthesis [35]. Of note, pacemaker requirement after TAVR also varies between different valve generations, and is influenced by the technique of implantation [36].

The Sinoatrial Node

For years, many were baffled by how the heart beats until the electrical conduction system of the heart was fully accounted for by the discovery of the SA node by Keith and Flack in 1907.12

The SA node is a group of specialized myocardial cells located at the junction of the superior vena cava and the right atrium close to the crest of the atrial appendage. The node consists of 2 types of myocytes: (1) the central nodal cells, arranged in a complex interdigitating manner with connective tissue, and (2) the transitional myocytes that change gradually from the typical pacemaker cells to ordinary myocytes.14

The location of the SA node was first described by Lewis and colleagues15 in 1910 and, later, confirmed on a canine model. In 1952, transmembrane potentials were first recorded from pacemaker cells of a frog heart.14 This finding was closely followed by the mammalian heart in 1955.16 These studies revealed that the most dominant feature of pacemaker cells is the spontaneous depolarization of the cell membrane. Further discoveries into the origin and function of pacemaker cells of the SA node occurred in 1963 when Trautwein and Uchizono17 discovered dominant pacemaker cells in rabbits. They determined that the origin of the heartbeat occurred in a small area (approximately 0.3 mm2), which contained about 5000 pacemaker cells that fire synchronously.14