Cardiac conduction

The Jim Moran Heart and Vascular Research Institute at Holy Cross Hospital in Fort Lauderdale, Florida, conducts cardiac research in collaboration with private corporations, university medical centers, and other research institutes. 

Cardiac arrhythmias or dysrhythmias are disturbances of the normal regular rhythm which may be caused by an abnormality in the site of impulse generation, its rate or regularity, or its propagation or conduction (1,2). The more commonly encountered cardiac arrhythmias are... 

The Class I agents decrease excitability, slow conduction velocity, inhibit diastoHc depolarization (decrease automaticity), and prolong the refractory period of cardiac tissues (1,2). These agents have anticholinergic effects that may contribute to the observed electrophysiologic effects. Heart rates may become faster by increasing phase 4 diastoHc depolarization in SA and AV nodal cells. This results from inhibition of the action of vagaHy released acetylcholine [S1-84-3] which, allows sympathetically released norepinephrine [51-41-2] (NE) to act on these stmctures (1,2). 

Hypokalemia. Hypokalemia associated with thia2ide diuretic therapy has been knpHcated in the increased incidence of cardiac arrhythmias and sudden death (82). Several large clinical trials have been conducted in which the effects of antihypertensive dmg therapy on the incidence of cardiovascular complications were studied. The antihypertensive regimen included diuretic therapy as the first dmg in a stepped care (SC) approach to lowering the blood pressure of hypertensive patients. 

Mechanisms of Cardiotoxicity Chemical compounds often affect the cardiac conducting system and thereby change cardiac rhythm and force of contraction. These effects are seen as alterations in the heart rate, conduction velocity of impulses within the heart, and contractivity. For example, alterations of pH and changes in ionic balance affect these cardiac functions. In principle, cardiac toxicity can be expressed in three different ways (1) pharmacological actions become amplified in an nonphysiological way (2) reactive metabolites of chemical compounds react covalently with vital macromolecules... 

Halogenated hydrocarbons depress cardiac contractility, decrease heart rate, and inhibit conductivity in the cardiac conducting system. The cardiac-toxicity of these compounds is related to the number of halogen atoms it increases first as the number of halogen atoms increases, but decreases after achieving the maximum toxicity when four halogen atoms are present. Some of these compounds, e.g., chloroform, carbon tetrachloride, and trichloroethylene, sensitize the heart to catecholamines (adrenaline and noradrenaline) and thus increase the risk of cardiac arrhythmia. 

Some metals, such as cadmium, cobalt, and lead, are selectively car-diotoxic. They depress contractivity and slow down conduction in the cardiac-system. They may also cause morphological alterations, e.g., cobalt, which was once used to prevent excessive foam formation in beers, caused cardiomyopathy among heavy beer drinkers. Some of the metals also block ion channels in myocytes. Manganese and nickel block calcium channels, whereas barium is a strong inducer of cardiac arrhythmia. 

Adenosine is produced by many tissues, mainly as a byproduct of ATP breakdown. It is released from neurons, glia and other cells, possibly through the operation of the membrane transport system. Its rate of production varies with the functional state of the tissue and it may play a role as an autocrine or paracrine mediator (e.g. controlling blood flow). The uptake of adenosine is blocked by dipyridamole, which has vasodilatory effects. The effects of adenosine are mediated by a group of G protein-coupled receptors (the Gi/o-coupled Ai- and A3 receptors, and the Gs-coupled A2a-/A2B receptors). Ai receptors can mediate vasoconstriction, block of cardiac atrioventricular conduction and reduction of force of contraction, bronchoconstriction, and inhibition of neurotransmitter release. A2 receptors mediate vasodilatation and are involved in the stimulation of nociceptive afferent neurons. A3 receptors mediate the release of mediators from mast cells. Methylxanthines (e.g. caffeine) function as antagonists of Ai and A2 receptors. Adenosine itself is used to terminate supraventricular tachycardia by intravenous bolus injection. 

Although blood pressure control follows Ohm s law and seems to be simple, it underlies a complex circuit of interrelated systems. Hence, numerous physiologic systems that have pleiotropic effects and interact in complex fashion have been found to modulate blood pressure. Because of their number and complexity it is beyond the scope of the current account to cover all mechanisms and feedback circuits involved in blood pressure control. Rather, an overview of the clinically most relevant ones is presented. These systems include the heart, the blood vessels, the extracellular volume, the kidneys, the nervous system, a variety of humoral factors, and molecular events at the cellular level. They are intertwined to maintain adequate tissue perfusion and nutrition. Normal blood pressure control can be related to cardiac output and the total peripheral resistance. The stroke volume and the heart rate determine cardiac output. Each cycle of cardiac contraction propels a bolus of about 70 ml blood into the systemic arterial system. As one example of the interaction of these multiple systems, the stroke volume is dependent in part on intravascular volume regulated by the kidneys as well as on myocardial contractility. The latter is, in turn, a complex function involving sympathetic and parasympathetic control of heart rate intrinsic activity of the cardiac conduction system complex membrane transport and cellular events requiring influx of calcium, which lead to myocardial fibre shortening and relaxation and affects the humoral substances (e.g., catecholamines) in stimulation heart rate and myocardial fibre tension. 

Cardiac IKi is the major K+ current responsible for stabilizing the resting membranepotential and shaping the late phase of repolarization of the action potential in cardiac myocytes. The name should not be confused with that of an Intermediate conductance calcium-activated K+ channel, which sometimes is also called IK1. 

Sites of endothelin-receptor expression. ETA receptors are expressed in the smooth muscle cells of the vascular medial layer and the airways, in cardiac myocytes, lung parenchyma, bronchiolar epithelial cells and prostate epithelial cells. ETB receptors are expressed in endothelial cells, in bronchiolar smooth muscle cells, vascular smooth muscle cells of certain vessels (e.g. saphenous vein, internal mammary artety), in the renal proximal and distal tubule, the renal collecting duct and in the cells of the atrioventricular conducting system. 

Clarkson CW, Hondeghem LM (1985) Mechanism for bupivacaine depression of cardiac conduction fast block of sodium channels during the action potential with slow recovery from block during diastole. Anesthesiology 62 396-405... 

Afferent input from cutaneous and visceral nociceptors is known to converge on spinal neurons, which accounts for the referral of pain between visceral and cutaneous structures (e.g. cardiac pain gets referred to the chest and left upper arm in patients suffering from angina pectoris). Projection neurons in the spinal dorsal horn project to cell nuclei in supraspinal areas such as the thalamus, brainstem and midbrain. Of these, the synaptic junctions in the thalamus play a very important role in the integration and modulation of spinal nociceptive and non-nociceptive inputs. Nociceptive inputs are finally conducted to the cortex where the sensation of pain is perceived (Fig. 1). The mechanisms via which the cortex processes nociceptive inputs are only poorly understood. 

T-tubule is a transverse invagination of the plasma membrane, which occurs at the specified sites characteristic to animal species and organs, i.e. at the Z-line in cardiac ventricle muscle and non-mammalian vertebrate skeletal muscle and at the A-I junction in mammalian skeletal muscle. It is absent in all avian cardiac cells, all cardiac conduction cells, many mammalian atrial cells and most smooth muscle cells. T-tubule serves as an inward conduit for the action potential. 

The skeletal muscle relaxants are contraindicated in patients with known hypersensitivity. Baclofen is contraindicated in skeletal muscle spasms caused by rheumatic disorders. Carisoprodol is contraindicated in patients with a known hypersensitivity to meprobamate. Cyclobenzaprine is contraindicated in patients with a recent myocardial infarction, cardiac conduction disorders, and hyperthyroidism, hi addition, cyclobenzaprine is contraindicated within 14 days of the administration of a monoamine oxidase inhibitor. Oral dantrolene is contraindicated in patients with active hepatic disease and muscle spasm caused by rheumatic disorders and during lactation. See Chapter 30 for information on diazepam. 

Flecainide (Tambocor) and propafenone (Rythmol) are examples of class I-C drags. These drugs have a direct stabilizing action on the myocardium, decreasing the height and rate of rise of cardiac action potentials, thus slowing conduction in all parts of the heart. 

During die initiation of therapy, patients taking propafenone must be monitored carefully. To minimize adverse reactions, dosage is increased slowly at a minimum of 3- to 4-day intervals. Periodic ECG monitoringis necessary to evaluate the effects on cardiac conduction. 

EDMD is another X-linked muscular dystrophy, clinically and genetically completely distinct from DMD and BMD. Affected boys usually have onset in childhood of contractures (especially involving the Achilles tendons, elbows, and spinal muscles), humeroperoneal muscle weakness, and cardiac conduction defects, which tend to be mostly a problem in adult life and may necessitate insertion of a pacemaker. The gene for EDMD is known to map to Xq28, but this localization is... 

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