Lesson 10 Flashcards
Speak about calcium homeostasis in the myocytes
Calcium homeostasis is important for the contraction of the myocytes and it is finally regulated. we have three major control mechanism of calcium:
- At the level of the sarcolemma: The sarcolemma is the membrane which surrounds the muscles fibers. Here the calcium flux is mediated by the sodium pump and the sodium-calcium exchanger.
- At the level of the sarcoplasmic reticulum: it represents the internal storage of calcium, here we have calcium channels modulated by inositol triphosphate. and we also have
- neurohumoral influences: control the flow of calcium, these are mediated by neurotransmitters, mainly by beta adrenergic signalling able to modulate calcium cycling through channels and transporters.
Starting from the sarcolemma, here we find three key proteins involved in calcium regulation:
- the sodium/potassium pump, which is also important because it maintains the balance between sodium and potassium, it lets sodium exit and potassium enter
- the sodium–calcium exchanger which is only able to work thanks to the sodium/potassium balance created by the sodium pump, since sodium gradient is its driving force. It brings one Ca2+ outside the cell in exchange for 3 Na+
- the calcium–ATPase also called calcium pump which helps extruding calcium from the cell, infact after contraction we have to gain back the original concentration of calcium.
When the heart contracts it is in need of calcium so we have that extracellular Ca2+ enters the cardiac myocyte through Ca2+ channels in the sarcolemma and this trigger induces the release of Ca2+ from the sarcoplasmic reticulum **into the cytosol, this mechanism is called induced Ca2+ release. The increased cytosolic Ca2+ facilitates myofibril contraction.
After the contraction it is time to relax, so The Na+/Ca2+ exchanger extrudes Ca2+ from the cytosol, using the Na+ gradient as a driving force and the Na+/K+ ATPase maintains the Na+ gradient by pumping sodium out of the cell, thus keeping the cardiac myocyte hyperpolarized. Since these proteins are important there is a mechanism of regulation, in fact during relaxation the sodium pump is tonically inhibited by the phospholemman. This is a protein that when is phosphorylated by PKA, which in turn is activated by cAMP, disinhibits the pump, thereby increasing sodium extrusion and indirectly enhancing the Na+ /Ca2+ exchange. Another important protein, this time found in the membrane of the sarcoendoplasmic reticulum is the SERCA (sarcoedoplasmatic reticulum Ca2+ ATPase). SERCA is normally inhibited by phospholamban. In this case as well the phosphorylation of phospholamban by PKA disinhibits the SERCA, allowing cytosolic Ca2+ to enter the sarcoplasmic reticulum in order to relax the cells.
Neurohumoral influences are also important to control calcium concertation, they are tied to adrenergic receptor signalling, infact beta1 adrenoreceptors are stimulants of the cardiac performance since most adrenergic receptors of the heart are b1 adrenoreceptors.
That means that beta1 agonists are able to increase calcium entry during systole, and because of their have inotropic effect we will have a higher stroke volume (amount of blood ejected during contraction). beta1 receptors also have positive chronotropic effect, so they increasing the beats. The two effect together will increase the cardiac output which depends on the heart rate and the stroke volume and describes how the heart ejects blood.
Beta1 receptors can be activated by a release of noradrenaline, this neurotransmitter infact is capable of increasing the effect of these receptors. Noradrenaline, on the other hand, can also act on the peripheral nervous system, where we find beta2 and alpha1 receptors. Beta2 receptors decrease systemic vascular resistance and thus increase the cardiac output while alfa1 increase the systemic vascular resistance SVR and the afterload. This means that the two receptors have opposite actions but there is a balance among them.
Speak about the pathophysiology of heart faillure, which are the 3 main causes at a cellular level?
Let’s now see the pathology of heart failure, and how the ability to contract can be impaired. Many disease processes can lead to myocyte dysfunction or death, causing replacement of the myocardium with fibrous tissue and leading to impaired contractility. So tissue replacement makes us lose part of the ability to contract. which are the causes of this?
- coronary artery disease CAD, which affects the arteries of the heart, **resulting in myocardial infarction, can produce necrosis of myocytes.
- systemic hypertension which is similar to CAD. These two are not directly related to the myocardial disease process.
- valvular heart disease, can impair the contractility and is the only situation directly related to heart diseases.
- A less common cause of the LV dysfunction is idiopathic cardiomyopathy, in which the main abnormality occurs at the level of the myocytes of the left ventricle which are not able to work correctly anymore.
Whatever the etiology, progressive contractile dysfunction of the myocardium leads ultimately to the syndrome of heart failure when not compensated. Heart failure can occur in the absence of contractile dysfunction too, so without contractility impairment. When this is the case we speak about diastolic heart failure, otherwise we have a systolic heart failure. **For example, several common cardiovascular disease are associated with abnormalities of LV relaxation and/or filling, indicating that the problem is related to relaxation, not contraction, and since we are not able to relax, the heart does not receive enough blood so we have decreased chamber compliance and elevated LV diastolic pressure. The two cases are also different under a morphological point of view:
in the diastolic heart failure we see an increased thickness of the muscle, while in the systolic heart failure we have thin and weak heart muscles.
At a cellular level, these pathophysiologic mechanisms are associated with decreased cardiac contractility caused by: dysregulation of calcium homeostasis, changes in the regulation and expression pattern of contractile proteins, and alterations in b-adrenoceptor signal transduction pathways. Let’s analyse these situations:
- Altered calcium homeostasis: when this happens **in failing cardiac myocytes, it can result in the prolongation of the action potential and of Ca2+ enhanced cytosolic concentration, associated with each contraction. The myocytes cannot control too well the concentration of calcium associated with a longer action potential, infact when we have a longer action potential we will have the release of calcium from its storage and an increased calcium concentration in the cytosol, at the same time there will be a depletion of Ca2+ in its storage areas. Also SERCA is no more able to work in a proper way since it remains inhibited by phospholamban, leading to the activation of a compensatory mechanism which is not as efficient as SERCA. This mechanism is the synthesis of new sodium calcium exchanger so that we have an increase in the number of these exchanger on the membrane of the sarcolemma. This situation impairs both systolic contraction and diastolic relaxation.
- Changes in the transcription of various genes in failing cardiac myocytes result in the synthesis of dysfunctional contractile proteins. To speak about this issue let’s make a hypothesis, let’s say that some myocytes enter a maladaptive growth phase reverting to the production of the fetal isoforms of some proteins. Why does this happen? Scientists think that this might happen because of a pseudo hypoxia situation in the cell. It is called pseudo because oxygen is still there but the cell is no more able to use it properly.
- another possibility is that the neurohumoral influencing are not able to influence well because of the desensitization of beta adrenergic receptors. This happens because of an increased noradrenalin release caused stress. This is a problem because beta adrenergic receptors are coupled to Gs proteins, and when they are desensitized they are not able to activate them anymore. Normally Gs proteins are able to activate adenylyl cyclase which then produces cAMP which is fundamental for PKA which in turn is fundamental for the activation of the ATPases which work on the relaxation pathway.
Speak about cardiac glycosides
Let’s start with cardiac glycosides. A doctor discovered by accident that plants called digitalis purpurea and digitalis lanata, also called foxgloves, could be used to produce a beverage able to control heart failure. At the time, the doctor knew of a driver of carriages who had edama on legs and a big belly, the doctor though that this person had maximum a year of life since there were no treatments for his condition. Surprisingly he saw him again a year later and he had improved his edema. The doctor decided to ask him about his improvements and the driver answered that a woman had given him a hot tea made with herbs which contained foxglove. Nowadays we also found another plant with similar effects called strophanthus gratus.
The compounds obtained from these plants can be administered orally and were initially named digitalis. The more important compounds of this family are digoxin and digitoxin, they act in the same why but digoxin has a time of action of 36h and digitoxin has a time of action of 7 days, from strophanthus we obtain another drug called ouabain.
All these compounds have a similar structure: a steroid nucleus, a glycosidic portion and a lactone moiety (porzione). This structure is fundamental for their action, thanks to it they are able to interact with the sodium/potassium ATPase, in fact all these drugs are able to block the ATPase when it is open on the extracellular potion, so when it is free to bind the two potassium ions. Only in this conformation it can get blocked by these agents and in this way there will be no sodium gradient, and we will see an increase of sodium in the cytosol, so calcium extrusion channels will work backwords introducing calcium in the cell and extruding sodium. This is good when we have not enough calcium and thus contraction is prevented, with these drugs in fact we have an increase in calcium concentration in the cytosol, which activates the extrusion of calcium and promotes contraction. That is why these drugs are inotropic agents, because they favour contraction by blocking the ATPase.
These compounds were also able to work in other districts, on neurons too, and if ATPase sodium potassium are blocked in the CNS. there will be an inhibition of the sympathetic flow and and increased parasympathetic flow, this is still good because it will slow down the heart rate allowing a better relaxation and a more efficient filling of the left ventricle.
These drugs were very used since a few years go, they have some side effects but were still very much used since they are orally active and easy to administer.
In particular digoxin alters the electrophysiologic properties of the heart by a direct action on the cardiac conduction system :
- It decreases the automaticity at the AV node causing a shorter action potential by accelerating the inactivation of L-type Ca2+ channels due to higher calcium concentration in the cytosol. So a decreased contraction and a slower heart rate increase the blood in the ventricle so we will have an increased stroke volume and efficiency of the heart.
- it enhances automaticity of the His and Purkinje conduction system, leading to a loss of intracellular K+, since ATPase is blocked, on top of the intracellular potassium accumulation. This will also slow the heart.
what are the problems of this drug? Digoxin has a narrow therapeutic window, so we have to constantly control the plasma concentration of digoxin, also because digoxin has therapeutic efficacy only when its concentration is between 0.5 and 0.8 ng/mL, while concentrations greater than 1.2 ng/ mL are associated with an increased mortality. The toxicity is caused by the potassium levels, so if we are having side effect we have to try and normalize plasma potassium levels.
Digoxin interacts with many drugs, **its **elimination mainly happens by renal excretion and involves P-glycoprotein. Other drugs used to treat heart failure, such as spironolactone, and some antidysrhythmic drugs use the same pathway, competing for it, which is a problem because people with both problems can end up with an altered potassium concentration.
(easy version:
- It can make the heart beat stronger and more efficiently by increasing the amount of calcium in the heart cells. This helps more blood leave the heart each time it beats (this is called increased stroke volume).
- It slows down the heart rate by acting on the electrical system of the heart, particularly at a place called the AV node, which is like a relay station that controls the signals that make the heart beat.
- It also increases the activity of the electrical pathways in other parts of the heart (His and Purkinje systems) but, at the same time, it causes the heart cells to lose potassium. Slowing the heart rate can be good for patients with certain types of fast heart rhythms.)
Speak about adrenergic receptor agonists to increase cardiac contraction and output
adrenergic receptor agonists are very useful because they are inotropic agents capable of increasing the rhythm of the heart. This is also a problem because an exaggerated heart rhythm can cause tachycardia, and that means that the heart is doing a lot of work and consuming more oxygen which can sometimes be a problem for people who can not provide this amount of oxygen to the heart, for ex people with a coronary artery diseases. For this and other adverse effects, the clinical use of sympathomimetic inotropes is generally reserved for the short-term support of the failing circulation due to their adverse effect profile. Sympathomimetic agents that stimulate myocardial b-adrenergic receptors share the adverse effect profile of tachycardia, arrhythmia, and increased myocardial oxygen consumption. In addition, they have a low oral bioavailability and must be administered by continuous intravenous infusion, this can only be done in hospitals for a few times in patients which are under medical control. These drugs con also interact with mono amino oxidase (MAO) receptors which are already used by antidepressants so it can be a problem if a patient has to take both drugs.
Among these drugs there is dopamine which is a precursor of adrenaline, and is able to bind to these receptors. The effect of dopamine change based on its dosage:
- At low doses, dopamine has a vasodilatory effect in the periphery by the stimulation of D1 receptors in the renal and mesenteric vascular beds. This regional vascular dilation reduces the impedance to left ventricular ejection.
- At intermediate doses, it causes vasodilation via stimulation of b2 receptors and also activates b1 receptors, thereby increasing contractility and heart rate.
- At higher doses, the activation of a1 receptors predominates in the periphery, leading to generalized vasoconstriction and increased afterload because we have interaction of dopamine with other receptors, for example it interacts with beta2 receptors, which dilates vases, and also interacts a little with beta1 which can increase the heart rate and contractility.
The drug dobutamine is preferred to dopamine since it only has beta receptor activity, but dobutamine is a racemic mixture, and depending on the isomer it can bind to other receptors like alpha1 and beta2, still these receptors compensate each other so we only have the beta receptors effect. Dobutamine is the sympathomimetic inotrope of choice for patients with acute cardiogenic circulatory failure.
Other drugs of the same kind that can be used are epinephrine, norepinephrine and isoproterenol.
Speak about non specific PDE inhibitors.
Years ago, in the 1960s, it was seen that non-specific PDE inhibitors have an inotropic effect, and were initially studied for asthma. PDE inhibitors increase cardiac contractility by increasing intracellular cAMP levels since they are normally decreased by PDE which are inhibited, thus this drug indirectly increases intracellular calcium concentration, that means that PDE inhibitors act as b1 agonists.
The inhibitors of PDE increase contractility and enhance the rate and extent of diastolic relaxation allowing the left ventricle to be filled with more blood generating a better contraction. Moreover PDE3 inhibitors also have vasoactive effects in the peripheral circulation, the cause decreased arterial tone and thus decreased afterload. The effect is a decreased impedance and decreased afterload, but it also decreases venous tone and thus the preload, so we have less blood in the heart. This problem a part all the other effects are useful. Since these inhibitors both vasodilate and increase contraction, so they have both an inotropic effect and vasodilation, they are considered ino-dilators.
This drug is great, however there is an increased mortality associated with longer term use of these agents which has restricted their role to the short-term managers of severe HF, so they are only used when patients need an immediate and intense treatment.
Also, although cardiac muscle expresses multiple PDE isoenzymes, selective inhibition of PDE3 has been shown to have beneficial cardiovascular effects. So it would be great to have a specific drug for PDE3
Speak about calcium sensitizing agents and new perspectives in the field of heart failure drugs
calcium sensitizing agents are newer drugs and we are still looking for better HF drugs. These agents are still being researched and some compounds like the novel class of positive inotrope, are still under investigation.
With these compounds scientists were trying to intervene on the contractile proteins, on their ability to interact with calcium and produce contraction. This can happen through augmented myocardial contractility caused by an enhanced sensitivity of troponin C; so these compounds enhance the sensitivity of troponin C to calcium thus increasing the interaction between actin and myosin.
levosimendan is on the market in some European countries, but not in the USA. This drug acts on the peripheral circulation, activating ATP-sensitive K+ channels, thus leading to peripheral vasodilation. So levosimendan can increase contractility of the heart and vasodilation entering the class of the inodilators.
FUTURE DRUGS FOR HEART FAILURE
Let’s summarize all the possible drugs used for HF:
- we might act on beta adrenergic receptors with catecholamines or PDE inhibitors, specifically PDE3 which is only present in the heart.
- We could also use cardiac glycosides, which able to act on NKA,
- there are some understudies on compounds that are focused on phosphlemman and phospholambdan.
- Also there are understudies on calcium sensitizer working on troponin C and sometimes Troponin I, which is the inhibitor of the action of troponin C interaction with calcium so we can inhibit Troponin I, this could be a good target in the future.
New classes of pharmacological agents are under investigation for their ability to augment myocardial contractility:
- drugs like cardiac myosin activators: studied for their ability to increase the efficiency of actin–myosin interactions.
- drugs like neuregulins: which can help synthetising contractile proteins
- drugs that can inhibit the effects of proinflammatory cytokines associated with HF, this has to do with age because inflammation has to do with a bunch of problems with the elders, it is called inflammaging.
- gene therapy methods to increase contractility, including the delivery of genes with cardiac-specific promoters that alter the production of contractile proteins, pumps, channels, and regulators in the heart. In rodents some experiments have been performed with phosphoamban and cardiac troponin I.
These approaches may improve cardiac contractility without increasing myocardial oxygen demand or significantly altering calcium signalling. This is important because in our hearts we have a perfectly balanced oxygen use and demand.
Why is the ammount of oxygen present in the heart so important?
Myocardial oxygen demand is the amount of oxygen that the heart requires to maintain an optimal function, while myocardial oxygen supply is the amount of oxygen provided to the heart by the blood which is controlled by the coronary arteries. In optimal physiologic conditions, myocardial oxygen demand does not exceed myocardial oxygen supply. This is why coronary blood flow is the major determinant of oxygen supply and is fundamental since there are no other ways to supply oxygen to the heart.
The heart, although it may not seem like it, is not a very oxygen perfused organ, actually in relation to its large metabolic needs, the heart is one of the most poorly perfused tissues in the body, and is therefore at greater risk of ischaemic damage. In normal people there is a balance which is also aided by our lifestyle, for example, exercise is important. Anyway in optimal conditions, we have a nearly 10-fold range between the condition of rest and the one of maximal exercise, so we have a wide ability to respond to possible altered needs of our heart.
In general, important factors for oxygen demands are: Heart rate, contractility, and ventricular-wall tension which are the three main factors, they determine myocardial oxygen demand. An increase in any of these variables requires the body to adapt to sustain adequate oxygen supply. In some situations, however, we may have that the oxygen demand might be significantly higher the supply. This causes ischemia, and the patient will feel chest pain.
