Linköping University | Department of Physics, Chemistry and Biology Bachelors thesis, 14 hp | Educational Program: Biology Spring term 2020 | LITH-IFM-G-EX—20/3861--SE
Mechanisms of action of β-blockers for the
treatment of heart failure
Jonas Burman
Examiner: Carlos Guerrero Bosagna Supervisor: Jordi Altimiras
Abstract
Heart failure is a syndrome in which the heart is unable to supply the entire body with oxygen. It is manifested in shortness of breath and exercise intolerance. One class of drugs that have proven effective in managing the progression of heart failure is β-blockers. These drugs bind to β-adrenergic receptors with high affinity, thus preventing the binding of endogenous catecholamines such as epinephrine and norepinephrine to the receptors by outcompeting them. The most common explanation of how β-blockers help manage the progression of heart failure is that by slowing the heart rate, it reduces the strain put on the heart. There may however be other ways that β-blockers help decrease morbidity and mortality of heart failure. Alternative reasons to how β-blockers aid the treatment of heart failure have been proposed based on the literature. It was found that the compensatory mechanisms intended to alleviate failure may be the main reasons that actually worsen it. Prolonged stimulation by epinephrine and norepinephrine damage the myocardium through oxidative damage, signaling for apoptosis and cardiac remodeling, as well as causing an increase in blood volume through the RAS-system. By blocking these maladaptive responses, β-blockers such as Carvedilol, Metoprolol and Nebivolol, together with other drugs such as ACE-inhibitors, and lifestyle changes help manage the progression of heart failure as well as increase the quality of life for the patients suffering from it
Date: 17/06/2020 Department of Physics, Chemistry and Biology
Linköping University
URL för elektronisk version
ISRN: LITH-IFM-G-EX—20/3861--SE
_________________________________________________________________ Title of series, numbering _20/3861___________________ Language Svenska/Swedish Engelska/English ________________ Report category Licentiatavhandling Examensarbete C-uppsats D-uppsats Övrig rapport _____________ Title:
Mechanisms of β-blockers in treating heart failure
Author: Jonas Burman
Keywords:
Contents:
1. Abstract ... 1
2. Introduction ... 1
3. Material and method ... 2
4. Results ... 3
4.1. Models for heart failure ... 3
4.2. Stimulation by the SNS can be detrimental ... 4
4.3. β-blockers ... 6
4.3.1. Other mechanism of action of β-blockers ... 8
5. Discussion ... 9
6. Social aspects ... 11
7. Ethical aspects ... 12
8. Acknowledgements ... 12
1. Abstract
Heart failure is a syndrome in which the heart is unable to supply the entire body with oxygen. It is manifested in shortness of breath and exercise intolerance. One class of drugs that have proven effective in managing the progression of heart failure is β-blockers. These drugs bind to β-adrenergic receptors with high affinity, thus preventing the binding of endogenous catecholamines such as epinephrine and norepinephrine to the receptors by outcompeting them. The most common explanation of how β-blockers help manage the progression of heart failure is that by slowing the heart rate, it reduces the strain put on the heart. There may however be other ways that β-blockers help decrease morbidity and mortality of heart failure. Alternative reasons to how β-blockers aid the treatment of heart failure have been proposed based on the literature. It was found that the compensatory mechanisms intended to alleviate failure may be the main reasons that actually worsen it. Prolonged stimulation by epinephrine and norepinephrine damage the myocardium through oxidative damage, signaling for apoptosis and cardiac remodeling, as well as causing an increase in blood volume through the RAS-system. By blocking these maladaptive responses, β-blockers such as Carvedilol, Metoprolol and Nebivolol, together with other drugs such as ACE-inhibitors, and lifestyle changes help manage the progression of heart failure as well as increase the quality of life for the patients suffering from it.
Keywords: Apoptosis, angiotensin II, β-antagonist, beta-blocker, Heart failure, Mechanism
2. Introduction
Heart failure affects over 23 million people worldwide according to Ponikowski and colleagues (2014), with about one in five people developing the condition some time during their life according to Lloyd-Jones and colleagues (Lloyd-Jones et al., 2002 cited by Ponikowski et al., 2014). According to predictions, the prevalence of heart failure is only going to rise, with the number in the United States of America being predicted to be over 8 million cases by 2030, compared to the about 5.7 million in 2012 (Heidenreich et al., 2013; Mozaffarian et al., 2015). This is an increase by 1.4 million cases even when adjusted for projected population growth (United States Census Bureau, 2012; Vespa et al., 2018)
β-blockers are drugs used to treat a wide range of conditions ranging from hypertension to preventing second myocardial infarctions following the first one (Whalen, 2019b). β-blockers work by preventing the activation of β-adrenergic receptors. These receptors usually bind
norepinephrine and epinephrine, which causes the physiological response associated with stimulation by the sympathetic nervous system (Whalen, 2019b). Activation of the
sympathetic nervous system leads to physiological responses including tachycardia, change in smooth muscle tone and activation of the renin-angiotensin system (Whalen, 2019a). The change in smooth muscle tone is caused by activation of α-adrenergic receptors, primarily α1
-receptors which induce smooth muscle contraction (Whalen, 2019a). This causes increase in blood pressure by peripheral vasoconstriction. Another function of α-receptors are the inhibition of norepinephrine release from pre-synaptic cells, though this is instead mediated by the α2-receptor and is an example of negative-feedback regulation (Whalen, 2019a).
Heart failure is the complex result of several conditions where the heart is unable to deliver adequate amounts of oxygen to the whole body (Katz, 2013; Whalen, 2019e). While it may never be cured it is possible to alleviate some of the symptoms. One of the leading theories on the cause of heart failure is that the ventricles are not getting properly filled, which is called diastolic dysfunction, this can be treated with beta-blockers that reduce the heart rate, allowing the ventricle to properly fill before the blood is expelled from the heart (López-Sendó et al., 2004). The reduction in heart rate is the most common explanation for the mechanism of action for β-blockers in treatment of heart failure. This may however not be the only mechanism through which β-blockers act to alleviate heart failure in patients as there are many different types of heart failure and reasons of the failure (Katz, 2013; Metra et al., 2010). In this review I will try to explain the mechanism as well as speculate on alternative mechanisms by which β-blockers help in preventing the progression of heart failure, focusing on compensated heart failure.
3. Material and method
This thesis is made in the form of a literature study in order to promote a deeper understanding on the subject of how β-blockers help to reduce mortality in heart failure patients. The literature study is based on secondary and primary literature found by using academic databases such as Google Scholar, PubMed as well as the university library’s resources at Linköping University. From these sources a summary of the literature was presented, and conclusions regarding alternative mechanisms explaining the mechanisms of β-blockers for treating heart failure were proposed.
4. Results
4.1. Models for heart failure
The different types of heart failure can be divided into acute and chronic heart failure. This is slightly misleading since there is no known cure for heart failure, meaning all cases are chronic. While all cases of heart failure can be deemed chronic, the difference between chronic and acute heart failure is that the acute heart failure is often a new or very serious case of worsening of heart failure, requiring urgent care (Kurmani & Squire, 2017). It may be caused by a myocardial infarction or weakening or damage to the chordae tendineae, the connective tissue in the heart that prevents regurgitation of blood back into the atria by holding the valve leaflets in place (Douedi & Douedi, 2020). Because more blood is entering the ventricle, it is forced to dilate to accommodate the increased influx of blood, to the point of reduced contractility (Waller & Sampson, 2018). Cardiac ischemia will also result in reduced contractility which results in reduced ejection fraction and thus, heart failure.
Heart failure can also be classified based on the ejection fraction (Ponikowski et al., 2016). The mean ejection fraction in healthy adults was found to be around 67 % in men and 68 % in women (Maceira et al., 2006). According to the 2016 European Society of Cardiology guidelines for treatment of acute and chronic heart failure, a left ventricular ejection fraction (LVEF) greater than, or equal to, 50% is deemed as heart failure with preserved ejection fraction (HFpEF) (Ponikowski et al., 2016). If the ejection fraction is instead between 49% and 40% , the heart failure is said to have mid-range ejection fraction (HFmrEF), and if the ejection fraction is below 40%, it is deemed to be heart failure with reduced ejection fraction (HFrEF) (Ponikowski et al., 2016). It is worth noting that in the study by Maceira and colleagues (2006), the sample size for each gender and age group was relatively small, with only 10 people in each group (Maceira et al., 2006). Nevertheless it can be hard to draw a line between HFpEF and a healthy heart based solely on ejection fraction.
As stated by Waller and Sampson (2018) “The underlying problem in heart failure is reduced cardiac output and therefore low blood pressure” (Waller & Sampson, 2018, p.133). To compensate for the low blood pressure there is an physiological compensatory increase in tone of the sympathetic nervous system, activation of the renin-angiotensin-aldosterone system (Waller & Sampson, 2018). If these changes are able to return the blood pressure to normal the heart failure is said to be compensated. If that is not the case, the heart failure is
deemed decompensated. Even in patients with decompensated heart failure, the sympathetic Kommenterad [CGB1]: This sentence can be splited for
nervous system will remain activated to a higher degree than in healthy individuals. In the European Society of Cardiology’s guidelines regarding treatment of heart failure, decompensated heart failure can often be the acute deterioration of the previously stable, compensated heart failure (Ponikowski et al., 2016).
4.2. Stimulation by the SNS can be detrimental
Because the sympathetic nervous system (SNS) is activated to a higher degree in these patients even at rest, their bodies lack the capability to meet their metabolic demands during times of stress or activity, which may in part be due to underperfusion of muscles from vasoconstriction (Lang et al., 1997; Middlekauff, 2005). The underperfusion may also cause ischemia and oxidative damage from changes in cell metabolism (Middlekauff, 2005)
Prolonged activation of the sympathetic nervous system will also cause receptor
desensitization. Receptor desensitization is when a prolonged or chronic stimulus does not result in the same level of cellular response as it previously did. An example is the decrease in response from continuous stimulus of β1-receptors by norepinephrine. The role of receptor
desensitization is to prevent the cell from over-responding to the ligand. Receptor desensitization can be achieved by downregulation of the receptor availability through receptor internalization and receptor uncoupling, as well as the reduced production of the receptor (Gainetdinov et al., 2004; Whalen, 2019d). In a review by Prijic and Buchhorn (2014), they write that the ratio of β1/β2-adrenergic receptor is 3:1 in normal adult hearts,
while it is closer to 1:1 in heart failure patients, mostly due to the downregulation of β1
-receptors (Port & Bristow, 2001 cited by Prijic & Buchhorn, 2014). This means there are three times more β1-adrenergic receptors compared to the number of β2-adrenergic receptors
in healthy adult hearts, while in heart failure the number of these different receptor subtypes are about even.
Changes in transcription can also affect the expression of β myosin heavy chain, where it shifts the expression from an isoenzyme with high ATPase activity, to one with lower ATPase activity (Lompre et al., 1979). Lombre and his team (1979) concluded this based on the shift from V1 myosin, which was the most common in healthy hearts, to V3 which were more
prominent in hypertrophic hearts. They claim that this might be the cause of reduced enzymatic activity since V3 has been shown to have lower activity than V1. A later study by
Lowes and colleagues (1997) supported this, stating that “changes in MHC isoforms are
Kommenterad [CGB2]: Redundant
Kommenterad [CGB3]: This sentence is confusing, please
candidates for the molecular basis of myocardial failure”, based on the decrease in expression of α and increase expression of β myosin heavy chain (Lowes et al., 1997). This is however not guaranteed as later studies have contested this finding, showing little difference in expression of isoforms between non-failing and failing adult hearts (Reiser et al., 2001).
Prolonged stimulation of β-adrenergic receptors will also lead to myocardial damage or cell death. In a study by Mann and colleagues, it was found that sympathetic stimulation could have deleterious effects on cardiomyocytes through cAMP-mediated calcium overload and a mismatch in oxygen demand and oxygen supply (Mann et al., 1992). Mann and colleagues (1992) used cardiomyocytes from adult cats and exposed them to norepinephrine
concentrations ranging from 10-9-10-6, since these concentrations were found to be
physiologically relevant (Cohn et al., 1984 cited by Mann et al., 1992). The team concluded that sympathetic stimulation was the cause of the cardiomyocyte damage since the reduced cardiomyocyte viability was concentration dependent from norepinephrine, as well as sensitivity to norepinephrine being tied to the density of β-adrenergic receptors in cardiomyocytes (Mann et al., 1992). Liang and colleagues (2000), speculated that the norepinephrine released due to the sympathetic stimulation was having direct toxic effects on cardiac nerves, but not through the same mechanism as proposed by Mann and colleagues (1992) (Liang et al., 2000). More specifically, the free radicals derived from norepinephrine were speculated to be the cause of myocardial nerve damage. By studying ferrets to which antioxidants were administered, they found that this was probably the case, as vitamin A, vitamin C and vitamin E all prevented the cardiotoxic effects of norepinephrine
administration, as well as the reduction in cardiac β-receptor density (Liang et al., 2000). This is of interest since the study by Mann and colleagues notes that they were not able to
comment on any potential effects of free radicals on their results in vitro (Mann et al., 1992).
Chronic stimulation of the sympathetic nervous system will lead to vasoconstriction and an increase in heart rate to increase cardiac output. While this does increase the stroke volume and contractility through β-receptor signaling, it may however not be enough to return contractility to normal. This means that even if the cardiac output is high enough at rest, the heart is unable to meet the oxygen demands when they are increased, such as during exercise. Arterial and venous vasoconstriction leads to increased filling pressure of the left ventricle, but if the heart is unable to expel the increased amount of blood, the hydrostatic pressure of the blood will build on until it surpasses the plasma oncotic pressure and thus lead to
Kommenterad [CGB4]: Redundant
Kommenterad [CGB5]: ‘Of free radicals on…’ or ‘free
radicals could have on…’ but not the two forms together
Kommenterad [CGB6]: Not be enough for what? To
produce a normal flow?
pulmonary edema (Waller & Sampson, 2018). Oncotic pressure is the osmotic pressure of large proteins, often proteins in a solution (Boron & Boulpaep, 2017, p. 128). The increase in stretch of the ventricle has also been proposed to cause apoptosis, or programmed cell death (Cheng et al., 1995).
Another result of sympathetic stimulation is increased release of renin by the juxtaglomerular apparatus (JGA) (Boron & Boulpaep, 2017, pp. 841–843). Renin acts by cleaving
angiotensinogen into angiotensin I, which then gets cleaved by the Angiotensin-cleaving enzyme (ACE) into Angiotensin II (ANGII). Angiotensin II then causes a wide range of actions that contribute to increase in blood pressure, for example by stimulating the release of aldosterone. Aldosterone causes the body to increase Na+ reabsorption by upregulation of
endothelial sodium channels in the collecting duct and distal tubule (Boron & Boulpaep, 2017, pp. 765–766). Angiotensin II also has other compensatory effects, such as
vasoconstriction and stimulation of thirst (Boron & Boulpaep, 2017, pp. 841–843; Inscho et al., 1997). These changes may be detrimental by causing an increase in the workload of the heart due to the vasoconstriction and increased blood volume. Angiotensin II has also been shown to induce apoptosis in rat cardiac cells, thus furthering the progression of heart failure (Kajstura et al., 1997)
4.3. β-blockers
As the name suggests, β-blockers work by being antagonists for β-adrenergic receptors and can be divided into selective and non-selective β-blockers. Being an antagonist means that it binds with high affinity to the receptor but has no intrinsic activity. Because they bind with higher affinity than they outcompete the endogenous catecholamines, thus preventing the signaling associated with catecholamine binding (Whalen, 2019c). Selective β-blockers bind to a specific subtype of β-receptor, while non-selective drugs bind to both β1 and β2-receptors
(Whalen, 2019b). An example of a selective β-blocker is Bisoprolol, which is a β1-selective
β-blocker that is used in patients suffering from hypertension. β1-selective β-blockers are more
safe for patients suffering from asthma as it has lower risk of inducing bronchoconstriction in these patients compared to non-selective β-blockers. When β-adrenergic receptors are blocked, the catecholamines only have α-adrenergic receptors to bind to and α-adrenergic receptors induce bronchoconstriction, which is the reason for asthma being a contraindication for treatment with β-blockers (Kotlyar et al., 2002; Morales et al., 2017; Schwartz et al., 1980). Of note is that β2-blockers are not used clinically (Whalen, 2019b).
Kommenterad [CGB8]: Split this sentence for readeability
Kommenterad [CGB9]: ….for treatment with B receptors. Kommenterad [CGB10]: It would be interesting to know if
Another type of β-blocker can be exemplified by Carvedilol and Labetalol. These two drugs are non-selective β-blockers with α1-blocking capabilities. This is important when treating
patients suffering from heart failure due to β1-selective drugs inducing initial vasoconstriction
in peripheral vasculature, which is not desired in patients already suffering from hypertension (Whalen, 2019b). Since α1-receptors are the reason for the initial vasoconstriction induced by
β1-selective drugs, vasoconstriction is avoided by blocking them (Whalen, 2019b). While
these drugs have α1-blocking action they may still be contraindicated to patients suffering
from asthma as the blockage may not be complete enough as to not yield a response (Kotlyar et al., 2002).
The β-blockers which the European Society of Cardiology recommends in patients with HFrEF are Carvedilol, Bisoprolol, Metoprolol and Nebivolol (Ponikowski et al., 2016). Metoprolol for example has been shown to be able to reduce the hospitalization rates by 32% compared to placebo, and was favoured in most treatment groups, see Fig.1 (Hjalmarson et al., 2000). Hospitalization rate is used as a marker for morbidity, but Metoprolol was also shown to decrease morbidity as percieved by patients and physicians (Hjalmarson et al., 2000).
Figure 1: Relative risk for total mortality or All-cause hospitalization and for total mortality or hospitality due to worsening heart failure in subgroups (based on figure from Hjalmarsson et al, 2000)
β-blockers are recommended to be used together with Angiotensin-converting enzyme-inhibitors (ACE-enzyme-inhibitors), because the renin-angiotensin-aldosterone axis causes an increase in the workload of the heart, and may thus be a good target of drugs treating heart failure (Whalen, 2019e). The European Society of Cardiology also states in their 2016 report that “There is consensus that β-blockers and ACEIs are complementary, and can be started together as soon as the diagnosis of HFrEF is made” (Ponikowski et al., 2016). However,
β-Kommenterad [CGB11]: These are really two sentences,
not one
Kommenterad [CGB12]: Not sure if I understand the
connection between this idea and what follows in the sentence.
Kommenterad [JB13R12]: It’s two different ways that the
blockers were not advised to be used in case of congestive or decompensated heart failure as these have not been thoroughly investigated (Ponikowski et al., 2016). In the case of congestive heart failure it was advised to treat the congestion through usage of diuretics and reaching a stable condition before starting β-blocker treatment (Ponikowski et al., 2014).
4.3.1. Other mechanism of action of β-blockers
The mechanism of β-blockers suggested by the European Society of Cardiology (2016) through which they prevent stimulation of β-adrenergic receptors does not differ. They all act by competitively antagonizing the receptors, thus preventing the binding of endogenous catecholamines (Whalen, 2019b). Two of the drugs suggested also have other effects besides β-blocking, the two being Nebivolol and Carvedilol.
Nebivolol is highly β1-selective drug that also has vasodilatory properties, which are due to its ability to stimulate release of nitric oxide (NO) (Bowman et al., 1994; Maffei & Lembo, 2009). Nitric oxide causes vasodilatation by binding to guanylyl cyclase in the cytosol, this binding stimulates the guanylyl cyclase, causing it to convert GTP into cGMP (Boron & Boulpaep, 2017, pp. 66–69). The cGMP then activates protein-kinase G which in turn leads to relaxation of the smooth muscle surrounding the peripheral blood vessels (Boron & Boulpaep, 2017, pp. 66–67). The increase in NO caused by the administration of Nebivolol may be due activation of β3-receptors since selective blockage of β3-receptors inhibited the NO production otherwise induced (Dessy et al., 2005). Nebivolol has been shown to increase endothelial Nitric oxide synthase (eNOS) translocation and phosphorylation, thereby increasing the production of nitric oxide (Ladage et al., 2006). Another theory is that the mechanism through which NO is produced is partly dependent on estrogen receptor as an estrogen receptor antagonist has been shown to decrease the vasodilatory effect of Nebivolol (Garbán et al., 2004; Ladage et al., 2006).
Besides the previously mentioned effect of β-adrenergic receptor blockade, Carvedilol has two different actions. Firstly, it also blocks α1-receptors, which means that it will help to decrease the vasoconstriction usually associated with α1-adrenergic stimulation (Whalen, 2019b). Secondly, it has been shown to protect the endothelium from oxidative damage, which is a regular finding in patients suffering from heart failure (Nakamura et al., 2002; Yue et al., 1993).
Kommenterad [CGB14]: These are really two sentences
and not one
Kommenterad [CGB15]: Blockade: the physical blocking
or surrounding of a place, especially a port, in order to prevent commerce and traffic in or out
5. Discussion
The primary mechanism through which β-blockers decrease the mortality and morbidity of patients suffering from heart failure is by preventing the prolonged β-adrenergic receptor stimulation from causing adverse effects such as cardiac cell apoptosis and cardiac
remodeling. This cell apoptosis can be caused by several different compensatory mechanisms induced in patients with heart failure. For example, the apoptosis can be induced by calcium overload, Angiotensin II release from the stimulation of β-adrenergic receptors by
norepinephrine, as well as the stretch caused by the increase in cardiac pre-and afterload (Cheng et al., 1995; Kajstura et al., 1997). The stretch-induced apoptosis may happen through a pathway involving calcium and nitric oxide synthase as proposed by Liao and colleagues (Liao et al., 2006). While Angiotensin II is also released from the stretching of the
myocardium, Liao and his team (2006) argue that the major cause of apoptosis is the calcium-dependent NO-cascade (Leri et al., 1998; Liao et al., 2006). This is interesting since
Nebivolol, a β-blocker recommended in patients with heart failure, stimulates the release of nitric oxide using the same enzyme as the calcium-dependent NO-cascades have been shown to have a detrimental impact on the myocardium and on endothelial nitric oxide synthase. This may mean that Nebivolol should be used to a lesser extent, or that it should not be used long-term. However, I was not able to find any sources on detrimental effects of Nebivolol in patients with heart failure, this may mean that the positives outweigh the negatives or that Nebivolol in some way does not trigger the negative effects of chronic exposure to nitric oxide mentioned by Liao and colleagues (2006).
As norepinephrine was shown to damage the myocardium by Liang and colleagues (2000), it would be interesting to investigate if using α2-adrenergic agonists could be used to decrease
the concentration of norepinephrine, since activation of α2-receptors inhibit the release of
norepinephrine. I suspect that there are underlying reasons as to why this is not mentioned as a possible treatment for heart failure, probably involving hypotension and sedation.
In their review on the mechanisms of action of β-blockers in heart failure, Prijic and Buchhorn (2014) mention a shift in prominence in α myosin heavy chain of the adult type to more of the β myosin heavy chain of fetal-type. This is of importance as the adult-type has higher ATPase activity compared to the fetal-type (Lombre et al., 1979 cited by Prijic & Buchhorn, 2014). They write that this may be a cause of the reduced contractility found in failing hearts, and that reversing it might be a mechanism through which β-blockers help
(Prijic & Buchhorn, 2014). A more recent paper by Reiser and colleagues (2001) supports this conclusion, finding a significant difference between the isoenzyme expression in failing and non-failing adult heart tissue.
β-blockers are not the perfect drug for treating heart failure however, as it cannot be used in all patients. One of the contraindications for blockers are already hypotensive patients, as β-blockers will cause a reduction in blood pressure. Specifically, α1-receptor blockage has the
risk of dizziness and orthostatic hypotension, or drop in blood pressure when standing up quickly (Whalen, 2019b). A very important contraindication for usage of β-blockers is asthma as β-blockers might cause bronchospasm in these patients. However some argue that using cardio selective, or β1-selective, drugs does not cause these adverse effects, while others argue
that even this selectivity is not enough (Kotlyar et al., 2002; Morales et al., 2017; Schwartz et al., 1980).
Though not perfect, the current understanding of heart failure suggests that a combination of treatments and changes to one’s lifestyle need to be used in managing heart failure. These treatments are highly individual as different people respond differently to different treatments, as well as heart failure arising due to different conditions. In patients suffering from heart failure with reduced ejection fraction, it is advised to use β-blockers as early as possible as it takes the longest to up-titrate and may have adverse effects on the short term but be beneficial once the dose has reached the target level. The starting doses are low as the body must adjust to the changes that they induce, such as hypotension, fatigue, and shortness of breath (Ponikowski et al., 2016). For this reason, up-titration of these usually means doubling the dose at most every two weeks until the target dose is reached, while carefully monitoring the patient (Ponikowski et al., 2016). The target dose for both Bisoprolol and Nebivolol suggested by the European society of Cardiology is 10 mg once per day. For Carvedilol the target dose is 25 mg twice per day, and for Metoprolol succinate, 200 mg once per day (Ponikowski et al., 2016). I speculate that the reason for the metoprolol succinate dose being so much higher compared to other drugs may partially be because it is an extended release formula. These types of formulas keep the plasma concentration relatively stable compared to drugs that do not have an extended release formula (Whalen, 2019f).
At the same time as β-blockers are given, it may also be fitting to administer ACE inhibitors or other drugs targeting the renin-angiotensin system. Using diuretics is also adviced because
Kommenterad [CGB17]: These are really two sentences
and not one
Kommenterad [CGB18]: Please, specify what is highly
individual: lifestyle?Management of heart failure?Treatments?
they help to reduce peripheral edema and help relieve symptoms of heart failure (Whalen, 2019e). Other drugs that may be helpful according to the European Society of Cardiology are mineralocorticoid receptor antagonists, angiotensin receptor neprilysin inhibitors and Ivabradine, depending on cause and condition (Ponikowski et al., 2016).
In conclusion, the reason why β-blockers help in reducing the morbidity of heart failure seems to be because the body’s compensatory mechanisms have detrimental effects on the health of the heart. By preventing these processes, the drugs help in managing the progression of the heart failure. These effects mostly stem from remodeling of the heart, cytotoxic effects of the derivates of catecholamines, mismatches in oxygen demand and oxygen supply, as well as the increase of wall stress due to compensatory mechanisms such as activation of the renin-angiotensin-aldosterone axis. For this reason, I agree with the European Society of Cardiology when it comes to starting the administration of β-blockers as early as possible. As far as I understand, ACE-inhibitors are already prescribed early but if that is not the case, it is the most obvious candidate in treatment of heart failure. Since heart failure is a lifelong condition, treatment is mostly focused on reducing morbidity and mortality, as well as improving the quality of life in the patients.
6. Social aspects
While we know today that β-blockers help decrease the morbidity and mortality of patients with heart failure, knowing the mechanism through which it works may help develop even better tools to help patients with heart failure. For example, finding ways to target the downregulation of β1-receptors induced by chronic sympathetic stimulation, or tools to
prevent myocardial damage caused by free radicals from increased norepinephrine
concentration could be ways to target specific causes of heart failure (Liang et al., 2000; Yue et al., 1993). This is of high importance since β-blockers may not be suitable for all patients. Usage of β-blockers is a very general treatment and comes with a range of contraindications and may cause unwanted effects to processes that are not a problem in certain patients. For example, β-blockers are contraindicated by patients suffering from asthma as they can induce bronchoconstriction from the activation of α-receptors (Kotlyar et al., 2002; Morales et al., 2017; Schwartz et al., 1980). However, even the β-blocker Carvedilol, a commonly used drug for the treatment of heart failure that blocks both β-adrenergic receptors as well as α1
-adrenergic receptors, is not suited for patients suffering from bronchial asthma, as the blockage on α1-receptors may not be adequate (Kotlyar et al., 2002).
Kommenterad [CGB19]: This is an incomplete sentence
Kommenterad [CGB20]: These are rally two sentences,
not one
7. Ethical aspects
The performance of clinical trials as well as any potential animal tests need to adhere to the international guidelines regarding clinical research and the animal welfare guidelines, respectively. An important aspect is that as with every clinical trial the goal is not to treat the participants of the trial but to further medical knowledge. This may lead to higher mortality and suffering in the patients to whom new treatments are administered but may yield much needed data, thus leading to better treatments for coming generations. It can also be argued that even experimental treatments should be allowed to a greater extent as the quality of life and survival rate in severe cases of heart failure is very poor, with a mortality rate of 50% within 5 years of the diagnosis (Mozaffarian et al., 2015).
8. Acknowledgements
I would like to thank Jordi Altimiras, my supervisor, for not only helping me find this subject and guiding me, but also for opening my eyes to the fascinating world of physiology during my time at LiU. I would also like to thank my opponents, Claud Yussif and Maryam Chaid, for helping me fix mistakes and help me better the text. A special thank you also goes out to Hanne Lovlie for supporting me while I was writing and for structuring the course. I would also like to thank all of my friends at for supporting me and pushing me to do better.
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Bowman, A., Chen, C., & Ford, G. (1994). Nitric oxide mediated venodilator effects of nebivolol. British Journal of Clinical Pharmacology, 38(3), 199–204.
https://doi.org/10.1111/j.1365-2125.1994.tb04342.x
Cheng, W., Li, B., Kajstura, J., Li, P., Wolin, M. S., Sonnenblick, E. H., Hintze, T. H., Olivetti, G., & Anversa, P. (1995). Stretch-induced programmed myocyte cell death. Journal of Clinical Investigation, 96(5), 2247–2259. https://doi.org/10.1172/JCI118280 Cohn, J. N., Levine, T. B., Olivari, M. T., Garberg, V., Lura, D., Francis, G. S., Simon, A. B.,
& Rector, T. (1984). Plasma Norepinephrine as a Guide to Prognosis in Patients with Chronic Congestive Heart Failure. New England Journal of Medicine, 311(13), 819–823. https://doi.org/10.1056/NEJM198409273111303
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