Docsity
Docsity

Prepare for your exams
Prepare for your exams

Study with the several resources on Docsity


Earn points to download
Earn points to download

Earn points by helping other students or get them with a premium plan


Guidelines and tips
Guidelines and tips

Mechanisms of β-blockers in Heart Failure: Apoptosis, Angiotensin II, and Receptor Desensi, Slides of Cardiology

The role of β-blockers in treating heart failure, focusing on the mechanisms of apoptosis, angiotensin II, and receptor desensitization. the causes of heart failure, the classification of heart failure based on ejection fraction, and the effects of sympathetic stimulation on cardiomyocytes. It also delves into the potential toxic effects of norepinephrine on cardiac nerves and the protective effects of antioxidants. Furthermore, the document discusses the proposed mechanisms of apoptosis, including calcium overload and the calcium-dependent NO-cascade.

What you will learn

  • What are the deleterious effects of sympathetic stimulation on cardiomyocytes?
  • How do antioxidants prevent the cardiotoxic effects of norepinephrine?
  • What are the leading theories on the cause of heart failure?
  • What are the proposed mechanisms of apoptosis in heart failure?
  • How is heart failure classified based on ejection fraction?

Typology: Slides

2021/2022

Uploaded on 09/12/2022

ekanaaa
ekanaaa 🇺🇸

4.3

(28)

268 documents

1 / 19

Toggle sidebar

This page cannot be seen from the preview

Don't miss anything!

bg1
Linköping University | Department of Physics, Chemistry and Biology
Bachelors thesis, 14 hp | Educational Program: Biology
Spring term 2020 | LITH-IFM-G-EX20/3861--SE
Mechanisms of action of β-blockers for the
treatment of heart failure
Jonas Burman
Examiner: Carlos Guerrero Bosagna
Supervisor: Jordi Altimiras
pf3
pf4
pf5
pf8
pf9
pfa
pfd
pfe
pff
pf12
pf13

Partial preview of the text

Download Mechanisms of β-blockers in Heart Failure: Apoptosis, Angiotensin II, and Receptor Desensi and more Slides Cardiology in PDF only on Docsity!

Linköping University | Department of Physics, Chemistry and Biology Bachelors thesis, 14 hp | Educational Program: Biology Spring term 20 20 | 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 /0 6 / 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 : Apoptosis, angiotensin II, β-antagonist, beta-blocker, Heart failure, Mechanism

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 α 1 - 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 α 2 - 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.

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 β 1 - 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 β 1 /β 2 - 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 β 1 - receptors (Port & Bristow, 2001 cited by Prijic & Buchhorn, 2014). This means there are three times more β 1 - adrenergic receptors compared to the number of β 2 - 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 V 1 myosin, which was the most common in healthy hearts, to V 3 which were more prominent in hypertrophic hearts. They claim that this might be the cause of reduced enzymatic activity since V 3 has been shown to have lower activity than V 1. 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 re-write

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? Kommenterad [CGB7]: Split this sentence for readability

Another type of β-blocker can be exemplified by Carvedilol and Labetalol. These two drugs are non-selective β-blockers with α 1 - blocking capabilities. This is important when treating patients suffering from heart failure due to β 1 - selective drugs inducing initial vasoconstriction in peripheral vasculature, which is not desired in patients already suffering from hypertension (Whalen, 2019b). Since α 1 - receptors are the reason for the initial vasoconstriction induced by β 1 - selective drugs, vasoconstriction is avoided by blocking them (Whalen, 2019b). While these drugs have α 1 - 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-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 authors chose to quantify morbidity

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 Kommenterad [CGB16]: redundant

(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 β-blockers are already hypotensive patients, as β- blockers will cause a reduction in blood pressure. Specifically, α 1 - 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 β 1 - 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 β 1 - 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 α 1 - adrenergic receptors, is not suited for patients suffering from bronchial asthma, as the blockage on α 1 - 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 Kommenterad [CGB21]: This sentence is incomplete

9. References Boron, W. F., & Boulpaep, E. L. (2017). Medical Pharmacology and Therapeutics (3rd ed.). Elsevier. 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/JCI 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/NEJM Dessy, C., Saliez, J., Ghisdal, P., Daneau, G., Lobysheva, I. I., Frérart, F., Belge, C., Jnaoui, K., Noirhomme, P., Feron, O., & Balligand, J. L. (2005). Endothelial β3-adrenoreceptors mediate nitric oxide-dependent vasorelaxation of coronary microvessels in response to the third-generation β-blocker nebivolol. Circulation , 112 (8), 1198–1205. https://doi.org/10.1161/CIRCULATIONAHA.104. Douedi, S., & Douedi, H. (2020). Mitral Regurgitation. In StatPearls. StatPearls Publishing. http://www.ncbi.nlm.nih.gov/pubmed/ Gainetdinov, R. R., Premont, R. T., Bohn, L. M., Lefkowitz, R. J., & Caron, M. G. (2004). DESENSITIZATION OF G PROTEIN-COUPLED RECEPTORS AND NEURONAL FUNCTIONS. Annu. Rev. Neurosci , 27 , 107–151. https://doi.org/10.1146/annurev.neuro.27.070203. Garbán, H. J., Buga, G. M., & Ignarro, L. J. (2004). Estrogen Receptor-Mediated Vascular Responsiveness to Nebivolol: A Novel Endothelium-Related Mechanism of Therapeutic Vasorelaxation. Journal of Cardiovascular Pharmacology , 43 (5), 638–644. https://journals.lww.com/cardiovascularpharm/Fulltext/2004/05000/Estrogen_Receptor_ Mediated_Vascular_Responsiveness.5.aspx Heidenreich, P. A., Albert, N. M., Allen, L. A., Bluemke, D. A., Butler, J., Fonarow, G. C., Ikonomidis, J. S., Khavjou, O., Konstam, M. A., Maddox, T. M., Nichol, G., Pham, M., Piña, I. L., & Trogdon, J. G. (2013). Forecasting the impact of heart failure in the united states a policy statement from the american heart association. Circulation: Heart Failure , 6 (3), 606–619. https://doi.org/10.1161/HHF.0b013e318291329a Hjalmarson, Å., Goldstein, S., Fagerberg, B., Wedel, H., Waagstein, F., Kjekshus, J., Wikstrand, J., El Allaf, D., Vítovec, J., Aldershvile, J., Halinen, M., Dietz, R., Neuhaus, K. L., Jánosi, A., Thorgeirsson, G., Dunselman, P. H. J. M., Gullestad, L., Kuch, J., Herlitz, J., … Deedwania, P. (2000). Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure: The metoprolol CR/XL randomized intervention trial in congestive heart failure (MERIT-HF). Journal of the American Medical Association , 283 (10), 1295–1302. https://doi.org/10.1001/jama.283.10. Inscho, E. W., Imig, J. D., & Cook, A. K. (1997). Afferent and efferent arteriolar vasoconstriction to angiotensin II and norepinephrine involves release of Ca2+ from intracellular stores. Hypertension , 29 (1 II), 222–227. https://doi.org/10.1161/01.hyp.29.1.

Kajstura, J., Cigola, E., Malhotra, A., Li, P., Cheng, W., Meggs, L. G., & Anversa, P. (1997). Angiotensin II induces apoptosis of adult ventricular myocytes in vitro. Journal of Molecular and Cellular Cardiology , 29 (3), 859–870. https://doi.org/10.1006/jmcc.1996. Katz, S. D. (2013). Definition of Heart Failure. In R. Baliga (Ed.), Heart failure: a practical guide for diagnosis and management. Oxford Univesity Press, Incorporated. Kotlyar, E., Keogh, A. M., Macdonald, P. S., Arnold, R. H., McCaffrey, D. J., & Glanville, A. R. (2002). Tolerability of carvedilol in patients with heart failure and concomitant chronic obstructive pulmonary disease or asthma. Journal of Heart and Lung Transplantation , 21 (12), 1290–1295. https://doi.org/10.1016/S1053-2498(02)00459-X Kurmani, S., & Squire, I. (2017). Acute Heart Failure: Definition, Classification and Epidemiology. In Current Heart Failure Reports (Vol. 14, Issue 5, pp. 385–392). Current Science Inc. https://doi.org/10.1007/s11897- 017 - 0351 - y Ladage, D., Brixius, K., Hoyer, H., Steingen, C., Wesseling, A., Malan, D., Bloch, W., & Schwinger, R. H. (2006). MECHANISMS UNDERLYING NEBIVOLOL-INDUCED ENDOTHELIAL NITRIC OXIDE SYNTHASE ACTIVATION IN HUMAN UMBILICAL VEIN ENDOTHELIAL CELLS. Clinical and Experimental Pharmacology and Physiology , 33 (8), 720–724. https://doi.org/10.1111/j.1440- 1681 .2006.04424.x Lang, C. C., Rayos, G. H., Chomsky, D. B., Wood, A. J. J., & Wilson, J. R. (1997). Effect of sympathoinhibition on exercise performance in patients with heart failure. Circulation. https://doi.org/10.1161/01.CIR.96.1. Leri, A., Claudio, P. P., Li, Q., Wang, X., Reiss, K., Wang, S., Malhotra, A., Kajstura, J., & Anversa, P. (1998). Stretch-mediated release of angiotensin II induces myocyte apoptosis by activating p53 that enhances the local renin-angiotensin system and decreases the Bcl- 2 - to-Bax protein ratio in the cell. Journal of Clinical Investigation , 101 (7), 1326–1342. https://doi.org/10.1172/jci Liang, C., Rounds, N. K., Dong, E., Stevens, S. Y., Shite, J., & Qin, F. (2000). Alterations by Norepinephrine of Cardiac Sympathetic Nerve Terminal Function and Myocardial β- Adrenergic Receptor Sensitivity in the Ferret. Circulation , 102 (1), 96–103. https://doi.org/10.1161/01.CIR.102.1. Liao, X., Liu, J., Du, L., Tang, A., Shang, Y., Wang, S. Q., Chen, L., Chen, Q., Liao, X., Liu, J., Du, L., Tang, A., Shang, Y., Wang, S. Q., Chen, L., & Chen, Q. (2006). Nitric oxide signaling in stretch‐induced apoptosis of neonatal rat cardiomyocytes. The FASEB Journal , 20 (11), 1883–1885. https://doi.org/10.1096/fj.06-5717fje Lloyd-Jones, D. M., Larson, M. G., Leip, E. P., Beiser, A., D’Agostino, R. B., Kannel, W. B., Murabito, J. M., Vasan, R. S., Benjamin, E. J., & Levy, D. (2002). Lifetime Risk for Developing Congestive Heart Failure. Circulation , 106 (24), 3068–3072. https://doi.org/10.1161/01.CIR.0000039105.49749.6F Lompre, A. M., Schwartz, K., D’Albis, A., Lacombe, G., Van Thiem, N., & Swynghedauw, B. (1979). Myosin isoenzyme redistribution in chronic heart overload. In Nature (Vol. 282). https://doi.org/10.1038/282105a López-Sendó, J., Swedberg, K., McMurray, J., Tamargo, J., Maggioni, A. P., Dargie, H., Tendera, M., Waagstein, F., Kjekshus, J., Lechat, P., Pedersen, C. T., Priori, S. G., Alonso García, M. A., Blanc, J.-J., Budaj, A., Cowie, M., Dean, V., Deckers, J., Fernandez Burgos, E., … Wallentin, L. (2004). Expert consensus document on β- adrenergic receptor blockers: The Task Force on Beta-Blockers of the European Society

Port, J. D., & Bristow, M. R. (2001). Altered beta-adrenergic receptor gene regulation and signaling in chronic heart failure. Journal of Molecular and Cellular Cardiology , 33 (5), 887 – 905. https://doi.org/10.1006/jmcc.2001. Prijic, S., & Buchhorn, R. (2014). Mechanisms of Beta-Blockers Action in Patients with Heart Failure. Reviews on Recent Clinical Trials , 9 (2), 58–60. https://doi.org/10.2174/ Reiser, P. J., Portman, M. A., Ning, X. H., & Moravec, C. S. (2001). Human cardiac myosin heavy chain isoforms in fetal and failing adult atria and ventricles. American Journal of Physiology - Heart and Circulatory Physiology , 280 (4 49-4). https://doi.org/10.1152/ajpheart.2001.280.4.h Schwartz, S., Davies, S., & Juers, J. A. (1980). Life-threatening cold and exercise-induced asthma potentiated by administration of propranolol. Chest , 78 (1), 100–101. https://doi.org/10.1378/chest.78.1. United States Census Bureau. (2012). Methodology and Assumptions for the 2012 National Projections. http://www.census.gov/population/projections/files/methodology/methodstatement12.pdf Vespa, J., Armstrong, D., & Medina, L. (2018). Demographic turning points for the United States: Population projections for 2020 to 2060. In Current Population Reports, P25- 1144. www.census.gov/programs-surveys/popproj Waller, D. G., & Sampson, A. P. (2018). Heart failure. In Medical Pharmacology and Therapeutics (pp. 131–142). Elsevier. https://doi.org/10.1016/B978- 0 - 7020 - 7167 - 6.00007- 5 Whalen, K. (2019a). Adrenergic Agonists. In R. Radhakrishnan (Ed.), Lippincott Illustrated Reviews: Pharmacology (7th ed., pp. 73–77). Wolters Kluwer. Whalen, K. (2019b). Adrenergic Antagonists. In C. Feild, R. Radhakrishnan, & S. Jinesh (Eds.), Lippincott Illustrated Reviews: Pharmacology (7th ed., pp. 94–95). Wolters Kluwer. Whalen, K. (2019c). Antagonists. In J. Peris (Ed.), Lippincott Illustrated Reviews: Pharmacology (7th ed., p. 32). Wolters Kluwer. Whalen, K. (2019d). Desensitization and down-regulation of receptors. In J. Peris (Ed.), Lippincott Illustrated Reviews: Pharmacology (7th ed., p. 27). Wolters Kluwer. Whalen, K. (2019e). Drugs for heart failure. In S. Anderson & K. V. Anderson (Eds.), Lippincott Illustrated Reviews: Pharmacology (7th ed., pp. 231–246). Whalen, K. (2019f). Lippincott Illustrated Reviews: Pharmacology (C. Feild & R. Radhakrishnan (Eds.); 7th ed.). Wolters Kluwer. Yue, T. L., Mckenna, P. J., Gu, J. L., Cheng, H. Y., Ruffolo, R. R., & Feuerstein, G. Z. (1993). Carvedilol, a new antihypertensive agent, prevents lipid peroxidation and oxidative injury to endothelial cells. Hypertension , 22 (6), 922 – 928. https://doi.org/10.1161/01.HYP.22.6.