mechanoelectrical properties

Question 1

Patch clamp identification of cardiac stretch–activated ion channels (SACs): who did it and what’s the implication

Answer 1

Sachs and coworkers,1 was pivotal not only for development of insight into mechanisms underlying cardiac mechano-electric transduction but also for advancement of a topic that had long been viewed as ‘‘artifact’’ or a matter of clinical curiosity, rather than a relevant component of cardiac electro-mechanic integration.

Question 2

what can electro-mechanical coupling explain?

Answer 2

Effects of SACs on cardiomyocyte electrophysiology are theoretically sufficient to quantitatively explain a majority of known acute manifestations of cardiac mechanoelectric transduction, both proarrhythmic and antiarrhythmic. Such plausibility does not confirm, of course, that SACs are the only, or even the major, contributor to mechanosensitive responses in cardiac electrophysiology.

Question 3

what does DIASTOLIC STRETCH generally cause for the membrane?

Answer 3

Diastolic stretch of cardiac tissue generally causes membrane depolarization (if the stretch is strong enough to induce any change), whether in working myocardium (where such depolarization may trigger PVB) or in conduction and pacemaker tissue

Question 4

what is the significance of the rate of rise in intensity of the mechano-stimulus?

Answer 4

●The rate of rise in intensity of transient mechanical stimuli enhances electrophysiologic efficacy.

Question 5

Franz and colleagues illustrated what?

Answer 5

The fact that mechanical stimuli of sufficient amplitude can be used to pace otherwise asystolic hearts has been elegantly illustrated by Franz and colleagues using Langendorff-perfused rabbit heart preparations in which the ventricles, rendered asystolic by ablation of the atrioventricular node, were stimulated by periodic inflation of an intraventricular balloon

Question 6

Energy levels required for mechanical PVB induction by precordial impact have been established by

Answer 6

Energy levels required for mechanical PVB induction by precordial impact have been established by defibrillation pioneer Zoll and colleagues in human volunteers as 0.04-1.5 J.

Question 7

what does the arrhythmogenesis require?

Answer 7

Arrhythmogenesis requires the combination of trigger and sustaining mechanisms, so that consequences of isolated ectopic beats, whether mechanically induced or not, usually are benign

Question 8

►Mechanical induction of PVBs also may occur as a result of the heart’s own contractile activity. evidence?

Answer 8

This phenomenon is illustrated by monophasic action potential (MAP) recordings from a patient undergoing pulmonary balloon valvuloplasty, a procedure whereby the stenosed right ventricular outflow valve is widened by insertion and inflation of a balloon. During balloon inflation, right ventricular contractions are isovolumic (no ejection) and give rise to significantly increased right ventricular peak pressures.

Question 9

commoto cordis is an example of what

Answer 9

Under certain conditions, acute mechanical stimulation alone is sufficient to give rise to both trigger and sustaining mechanisms for maintained arrhythmias, even in otherwise healthy myocardium

Question 10

what are the risk factors for commoto cordis?

Answer 10

Key risk factors are
(1) type of impact (impulse-like stimulation whose arrhythmogenic risk is inversely related to projectile compliance and contact area),
(2) impact location (chest areas that offer efficient energy transmission from body surface to myocardium),
(3) impact energy (large subcontusional forces, reaching >100J in competitive sports),
(4) impact timing (before peak of the ECG T-wave).
►►The first three factors may be regarded as permissive: Only if they are present does timing become decisive, which may explain why the vast majority of chest impacts result in relatively benign heart rhythm changes, if any.

Question 11

why is arrhythmogensis favoured in that short period of cardiac repolarisation ?

Answer 11

Quantitative model considerations suggest that arrhythmogenesis is favoured, during this narrow time window, by critical overlap of the mechanically stimulated tissue region with the trailing end of the excitation wave.20,21 Sustained arrhythmogenesis occurs when, in addition to mechanical induction of PVBs in myocardium that has regained excitability (trigger), the intersection of mechanically affected myocardium and the trailing repolarization wave gives rise to a functional block zone around which reentry can develop (sustaining mechanism).

Question 12

what about chronic cardiac overload?

Answer 12

In contrast with these acute stretch effects, contributions of mechano-electric transduction to arrhythmogenesis in chronic cardiac overload are more difficult to uncover. ►Usually, pathologic conditions that involve cardiac pressure or volume overload tend to develop relatively slowly, and they are associated with pronounced structural and functional remodeling of the myocardium. The causes of both overload and tissue remodeling may be proarrhythmogenic in their own right. Nonetheless, mechanical factors have been implicated in the domestication of atrial fibrillation, 22 and in ventricular arrhythmogenesis in pressure- or volume-overloaded hearts.

Question 13

what does valsalva maneouvre do?

Answer 13

A conceptually interesting approach to probing the relevance of mechanical factors for arrhythmogenesis in the chronically overloaded heart is the temporary removal of tissue distention—
by the Valsalva maneuver (an attempt to forcefully exhale against the closed glottis). ►►Intrathoracic pressure increases during the strain phase of the maneuver, reducing venous return and favoring arterial drainage from the chest, which leads to a measurable reduction in cardiac dimensions. On this background, ventricular tachycardia can be converted to sinus rhythm

Question 14

valsalva maneuvre - does it act throught mechanic or is it vagally mediated?

Answer 14

►Relief of ventricular wall stress, rather than autonomic nervous system–mediated responses, appears to be a causal contributor to this antiarrhythmic effect, because successful cardioversion also can be observed in the presence of pharmacologic or surgical denervation of the heart (as in transplant recipients).25
►►Thus, acute diastolic stretch can trigger ectopic excitation, and systolic or sustained stretch may contribute to arrhythmia sustenance by causing heterogeneity in excitability, refractoriness, and electrical load. These observed effects have implications for preventive measures (chest protector design), as well as for interventions such as hemodynamic unloading, active and passive cardiac assist, biventricular pacing, or defibrillation, when defibrillation threshold increases with ventricular preload.

Question 15

mechanical termination of arrhythmia (acute)

Answer 15

Acute mechanical stimulation, usually by precordial thump, can be used as a means of advanced cardiopulmonary resuscitation to terminate arrhythmias, including ventricular asystole, ventricular tachycardia, and ventricular fibrillation

Question 16

The energy levels required for precordial thump–based termination of ventricular tachycardia and ventricular fibrillation are …

Answer 16

The energy levels required for precordial thump–based termination of ventricular tachycardia and ventricular fibrillation are….. one to two orders of magnitude higher than those involved in fist pacing of the asystolic ventricle (4 to 10 J versus approximately 0.04 to 1.5 J in the adult), and these more powerful thumps are applied preferentially to the lower sternum, rather than the left sternal edge (which tends to be targeted by fist pacing and precordial percussion).

Question 17

Precordial thump for termination of tachyarrhythmias is believed also to act primarily how>?

Answer 17

by depolarizing excitable tissue

Question 18

chronotropic response to stretch in humans illustrated how and by whom?

Answer 18

the identification of a positive chronotropic response to stretch in humans until Donald and Shepherd dissociated the increase in venous return from arterial pressure changes by passively elevating the legs of healthy volunteers in supine position, confirming the positive chronotropic response in humans.42

Question 19

respiratory sinus arrhythmia mechanism?

Answer 19

Cardiac mechano-electric transduction also is believed to underlie the component of respiratory sinus arrhythmia (RSA) that is independent of the autonomic nervous system. ►Here, dynamic changes in thoracoabdominal pressure gradients favour venous blood return to the heart during inspiration, causing a relative increase in right atrial filling and an associated rise in heart rate.
►Although this mechanical component contributes little to RSA at rest (when modulation of vagal innervation is the dominant driver), it becomes a major cause of RSA during peak exercise in healthy subjects (when vagal tone is reduced while respiratory effort and associated pressure gradient changes are enhanced),43 as well as in transplant recipients.

Question 20

Mechanosensitive ion channels can be found in

Answer 20

in most prokaryotic and eukaryotic cell types

Question 21

TYPES OF MECHANOSENSITIVE ION CHANNELS in the mammalian heart

Answer 21

The mammalian heart contains ion channels that are activated by stretch in the absence of cell volume changes (SACs), and cell volume-activated channels (VACs).

Question 22

how quickly do sacs and vacs respond to stimuli?

Answer 22

►SACs respond to mechanical stimuli within milliseconds, ►whereas VACs tend to show a significant lag time (minutes) between the onset of cell volume changes and ion channel activation.

Question 23

what are SACs implicated in?

Answer 23

due to rapid response, SACs have been implicated as a substrate underlying electrophysiologic responses to dynamic changes in the cardiac mechanical environment, whereas VACs are understood to contribute in chronic settings such as (post)ischemic swelling or hypertrophy (in which VACs are constitutionally active).

Question 24

are SACs selective? how does that affect their reversal potentials?

Answer 24

SACs either show little selectivity for (predominantly monovalent) cations (SACNS, for nonselective) or preferentially conduct potassium ions (SACK). ►These selectivity profiles determine their transmembrane current reversal potentials, which are halfway between action potential plateau and resting potentials for SACNS (usually between 0 and -30 mV) or ►close to the potassium equilibrium potential for SACK (approximately -95 mV).

Question 25

►Like other ‘‘descriptive’’ ion channel classifications, these categories are not absolute, and overlap with other types of ion channels is inevitable, as several mechanosensitive ion channels also are voltage- or ligand-sensitive (and vice versa).
GIVE EXAMPLES

Answer 25

Thus, the hyperpolarization-activated cyclic nucleotide–sensitive channel (HCN) is mechanically modulated, as is the adenosine triphosphate (ATP)-inactivated potassium channel (KATP), whose open probability is increased by stretch in atrial and ventricular myocytes.

Question 26

what can mechanosensitivity explain about studies in vitro vs in vivo

Answer 26

Mechanosensitivity may explain why these two ion channel populations appear to be less active when studied in vitro, compared with their expected behavior in situ. ►►The contribution of the funny current, if (HCN equivalent of cardiac pacemaker cells), to pacemaking, for example, could be underestimated under conditions of reduced external load (as is normally the case for isolated cell and tissue preparations).

Question 27

what stimuli do SACs respond to? and how?

Answer 27

SACs respond to a range of external stimuli: local membrane deformation, changes in cell curvature, lateral compression, and axial stretch.
►Whether transfer of mechanical energy to the ion channel protein occurs mainly via the cytoskeleton or the lipid bilayer is a matter of debate (in all likelihood, both are involved, to individually varying degrees). Some SACs (such as a transient receptor potential channel [TRPC1]) can be activated mechanically in pure lipid bilayers.51 Other SACs are sensitive to cytoskeletal integrity, which may either promote or prevent channel openings

Question 28

pharmacological probes for SACs

Answer 28

►►In the absence of direct access to several of the relevant ion channel populations by the patch clamp technique, SAC contributions to cardiac electrophysiology have been studied by pharmacologic block, largely using the ionic form of gadolinium (Gd3+) (typically 10-100 mM), aminoglycosidic antibiotics (e.g., streptomycin, in a dose of 30 to 50 mM), or a tarantula venom peptide, Grammostola spatulata mechanotoxin (GsMTx-4).

Question 29

drawbacks of gadolinium

Answer 29

Gadolinium suffers from a lack in specificity overlapping concentration range for block of L-type calcium, sodium, and rapid delayed rectifier potassium channels, as well as of the Na+-Ca2+ exchanger), and precipitation in bicarbonate- or phosphatebuffered solutions (although it is possible that both Gd3+ and gadolinium salts may affect SACs).

Question 30

drawbacks of aminooglycosides

Answer 30

►Aminoglycosides are not strictly selective (e.g., L-type Ca channel block with a half-maximal inhibitory concentration, IC50, of 1 to 2 mM), nor are they necessarily reliable tools for acute SAC block in situ (if they were, they would be unlikely to be prescribed as antibiotics)

Question 31

drawbacks of GsMTx-4

Answer 31

GsMTx-4—although highly selective and effective in both D and L configurations—suffers from limited availability and high cost.

Question 32

SACs effects on cellular electrophysiology depend on…?

Answer 32

depend on the effective stretch target (SACNS, SACK) and stretch timing relative to the cardiac cycle, as well as on rate of rise, amplitude, and profile of the stimulus.

Question 33

In spite of recent progress in the description of SACs and their effects on cardiac mechano-electric transduction, the list of open questions is long. To name but a few:

Answer 33

Current mechanical stimulation techniques generally are limited in their ability to control levels of stress or strain applied to individual cells or channels.
►The question whether stress or strain is the key modulator of SAC opening remains unanswered.
►Although the molecular-genetic identity of mammalian cardiac SACs is beginning to emerge, proteomic insight into channel structure and function is still scarce.
►The roles of regional differences in mechano-electric transduction, tissue heterogeneity, nonmyocyte cellular contributions, and so on, all are ill explored.
►Changes during development, aging, and disease are only beginning to be addressed.
►Pharmacologic tools for modulating SAC activity are neither organ-specific nor able to target individual cell types or disease states, and they suffer from a range of limitations that restrict their use in systemic investigations.
► Techniques to report electrophysiologic effects of in situ SAC activation should provide cell type–specific signals with high spatiotemporal resolution, perhaps through development of genetically encoded fluorescent markers.