Trials documenting improvement in cardiovascular outcomes and reduced cardiovascular mortality with renin-angiotensin-aldosterone system inhibition.
\r\n\t
",isbn:"978-1-80356-477-7",printIsbn:"978-1-80356-476-0",pdfIsbn:"978-1-80356-478-4",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"b306ce94998737c764d08736e76d60e1",bookSignature:"Dr. Alyssa A Brewer and Dr. Brian Barton",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11636.jpg",keywords:"Mammalian, Primate, Human, Genetics and Epigenetics, Individual Variability, Adaptation, Cortical Reorganization, Cortical Recovery, Visual Field Map, Sensorimotor Maps, Bottom-Up Sensory Processing, Top-Down Visual Attention",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 3rd 2022",dateEndSecondStepPublish:"May 4th 2022",dateEndThirdStepPublish:"July 3rd 2022",dateEndFourthStepPublish:"September 21st 2022",dateEndFifthStepPublish:"November 20th 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"2 months",secondStepPassed:!0,areRegistrationsClosed:!1,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Dr. Brewer is a Stanford-trained physician-scientist, tenured Associate Professor at UC Irvine, and Director of the mind space Lab, who uses cutting-edge computational neuroimaging to study the organization and plasticity of the human sensory cortex.",coeditorOneBiosketch:"Dr. Barton is a UCI-trained cognitive scientist who has pioneered the study of auditory field maps in the human cortex and currently focuses his research on computational neuroimaging measurements of audiovisual cortical processing and organization.",coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"115304",title:"Dr.",name:"Alyssa",middleName:"A",surname:"Brewer",slug:"alyssa-brewer",fullName:"Alyssa Brewer",profilePictureURL:"https://mts.intechopen.com/storage/users/115304/images/system/115304.jpg",biography:"Dr. Alyssa A. Brewer completed her undergraduate degrees at Stanford University, with a B.S. with Honors in Biological Sciences and an A.B. in Comparative Literature with interdisciplinary Honors in Humanities. She continued on at Stanford in a dual-degree graduate program, graduating with an M.D. and a Ph.D. in Neuroscience in 2007. Her work in graduate school with Brian Wandell, Ph.D., focused on computational neuroimaging measurements of visual cortex organization and plasticity in humans and macaque. She now is an Associate Professor in the Departments of Cognitive Sciences and Language Science, by courtesy, at the University of California, Irvine. Dr. Brewer’s research focuses on visual, auditory, and multi-sensory neuroscience, using behavioral, genetic, and high-resolution neuroimaging techniques to investigate questions ranging from the fundamental organization of human visual and auditory cortex to plasticity in visual, auditory, and sensorimotor regions.",institutionString:"University of California, Irvine",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"6",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"University of California, Irvine",institutionURL:null,country:{name:"United States of America"}}}],coeditorOne:{id:"149246",title:"Dr.",name:"Brian",middleName:null,surname:"Barton",slug:"brian-barton",fullName:"Brian Barton",profilePictureURL:"https://mts.intechopen.com/storage/users/149246/images/system/149246.jpeg",biography:"Dr. Brian Barton received his B.S. in Psychology at the University of Oregon, where he studied visual attention and working memory with Edward Awh, Ph.D., and Edward Vogel, Ph.D. Dr. Barton then earned his Ph.D. in Psychology with a Concentration in Cognitive Neuroscience in 2013 at the University of California, Irvine (UCI), where he expanded his research into functional MRI measurements of visual cortex organization and plasticity with Alyssa A. Brewer, M.D., Ph.D. He continued on at UCI as a post-doctoral scholar for three years with Drs. Brewer, Greg Hickok, Ph.D., and Kourosh Saberi, Ph.D., applying his vision work to measurements of the organization of human auditory cortex. 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Each year, fraud causes significant losses to the shareholders and creditors of the targeted companies, which hinders the proper functioning of the capital markets. Fraud is generally committed by executives who are very often involved and are subject to legal action by financial market regulators.
The revelation of a fraud tarnishes the reputation of several participants in the financial markets, thereby affecting investor confidence in the market and penalizing all businesses [1]. In fact, any fraud announcement leads investors to question the competence and vigilance of financial market regulators, and even auditors, financial analysts, boards of directors, and credit rating agencies, all these actors have their share of responsibility.
In addition to the financial losses suffered by investors, other losses are added, such as the socio-economic costs related to job losses [2], and can even go as far as the disappearance of the whole entity. But the question that arises is as follows: Given the financial losses and reputation suffered, why do business leaders or entrepreneurs engage in fraud and manipulation? Can we determine the individual and organizational responsibilities that lead to fraud committed by leaders and entrepreneurs?
What tools and strategies are available to a board of directors to detect and prevent such fraudulent practices? We will try to answer these questions, by proceeding as follows: we will first carry out a synthesis of the main types of fraud committed by managers. Secondly, the motivations of the main actors and to identify the attributes, whatever it is individual or organizational likely to lead to fraud. Third, we will focus on the profile of the fraudulent leader. And finally, we will present the recommendations for the various actors responsible for the integrity of the financial markets which are the boards of directors, the regulatory bodies, the accountants, and the auditors.
Fraud or embezzlement committed by business leaders can take many forms but often boil down to the following maneuvers:
misappropriation of assets;
manipulation of financial results; and
lack of disclosure, incomplete or misleading disclosure.
Misappropriation of assets is mainly carried out by means of the so-called related party transactions where the offending manager initiates commercial or financial transactions between the company he manages and the subsidiary companies [3]. For example, a holding company may carry out several transactions with companies or entities controlled by the members of its management team, allowing them to make significant gains. So the leaders could profit and transfer several millions to companies that they personally created. This investment strategy cannot be controlled or approved by the board of directors. Managers can therefore be led to invest even in companies in liquidation, without anyone controlling them, and the discovery by the board of this misappropriation of an unauthorized action of the funds of the company would not have heavy punishment; the offending manager will simply be dismissed.
The manipulation of financial statements most often relates to an excessive or excessively exaggerated recognition of revenue, and an undervaluation of operating expenses or an overvaluation of assets [4]. The extent of accounting and financial manipulation by companies is difficult to pin down due to the multitude of events, prosecutions, and counter-prosecutions that have characterized this file. However, according to the information available, it generally seems difficult to verify accounting or financial information such as the increase in profits. Indeed, a swelling generally reflects the nonrecognition of certain operations or even an overvaluation of negotiable securities, tax credits receivable.
When the disclosure of financial and accounting information, which should be made by the officers of the companies, is absent or misleading, the companies may be liable to fines of up to millions. What is certain, acts of fraud such as embezzlement and manipulation could not have existed if the company’s disclosure practices had been carried out in accordance with the rules and the transparency required by the regulations [5]. For example, we disclose financial information in the balance sheet which will give information on marketable securities classified as current assets. However, these securities are not really negotiable or cashable in the short term, but their recovery can be spread over several years. To detect these anomalies or to verify the authenticity of this information, it is necessary to analyze the notes of the financial statements and compare them with the balance sheets and the financial statements.
Thus, certain information disclosed may be disguised or unrealistic, especially in the case of accounting for transactions between the parent company and its subsidiaries; indeed certain transactions have not been properly accounted for and presented in its previous financial statements.
The errors that are generally made concerned mainly the following elements in previous periods:
products;
cost of goods sold;
selling fees;
general and administrative costs;
depreciation of fixed assets;
interest expense;
exceptional items;
charge of income taxes;
tax credits receivable;
production costs;
related party accounts receivable;
fixed assets; and
creditors and charges payable and income taxes receivable.
In a few months, following the announcement of various allegations of fraud and embezzlement, the action plummeted and then the company was sold. In most cases, the companies have either declared bankruptcy and been wound up or undergone a judicial restructuring where the shareholders have lost everything.
In addition to financial losses, leaders certainly lose their leadership positions, control of their business, and especially their reputation [6].
How did they commit the frauds they were accused of while the company was open with a board of directors made up of influential people? Why did they go down that path, risking everything they had worked for? In general, a manager or entrepreneur will engage in fraud if the organizational context is favorable to commit fraud and also if the manager displays a profile likely to commit the act of fraud.
The opportunity to commit fraud arises when controls are absent or even failing. Thus, fraud will be easier to carry out since the manager will be free and without control within the company. Indeed, senior managers who can circumvent existing controls, especially if the external governance mechanisms such as regulations, or internal ones such as the board of directors, are insufficient or even ineffective [7]. When they commit fraud, the managers of a company know very well the administrative machinery and have access to data and systems, and when the latter are involved and part of the shareholders, this will make them in a position of strength, while reducing the role of the board of directors to which they belong. Managers can therefore exercise absolute control over the company. It can therefore be said that there was no counterweight to their authority within the company. For example, the CEO can be a more or less significant shareholder, which gave him an edge over the other members of the board of directors.
Another opportunity that favors fraud is the pressure geared toward high performance; this generally manifests itself during stock market bubbles. In fact, rapid deflations of stock market bubbles are very often accompanied by the manifestation of fraud committed by business managers [8]. Indeed, the stock quotes of several companies always reflect expectations of optimistic profits, which implies very high growth rates. Any profit announcement that does not meet stock market expectations will result in a sharp drop in the stock price. In this context, if the performance of the company begins to decline, the management of the company will be forced to manipulate the accounting results to ensure that the earnings per share announced meet or even exceed market expectations. Investors then imposed a stock market valuation, at an increasing, unrealistic rate, which pushes managers to fraud, by favoring accounting manipulations. Also, the stock market bubble will be liable to lead to fraud or manipulation of the financial statements if the directors have a remuneration strongly focused on the appreciation of the stock market price or focused on results or profits.
In addition to the organizational context, the manager’s psychological profile can lead him to commit fraud. Indeed, some research on criminological thinking on financial fraudsters have agreed that there are psychological peculiarities specific to financial fraudsters, which are very similar to the peculiarities of the psychopath [9]. In fact, like all psychopaths, specialized fraudsters always give the image of a healthy, rational, and apparently normal personality, which would mask their true nature.
In order to recognize the psychopathic fraud leader, three aspects of the leader’s profile are typical: always having a rationalizing speech in order to justify their actions, and an arrogant attitude.
The people implicated in a fraud are always able to justify their action by minimizing the extent of its serious consequences.
The fraudulent leader has the ability to rationalize bad decisions that are not even ethical.
Fraud also has a dimension attached to the attitude of individuals. Indeed, engaging in fraud at the risk of collapsing a society reflects an attitude of trust, arrogance, and exaggerated narcissism on the part of fraudulent leaders. Such leaders will first favor a centralized decision-making process in their hands, persistence, and stubbornness to pursue their strategies. These leaders will be free from anxiety because they are convinced that ultimately their will and their decision will prevail [10]. It can therefore be said that an ambitious, arrogant, and self-confident leader always engages in fraud by never thinking that he will be caught. According to them, the controls or the people responsible for prevention or detection are of lower intelligence.
They always do so, the first successful fraud will reinforce the behavior to be pursued in this way of fraud. It will continue to make decisions unilaterally and centrally. Relations with collaborators and employees are very superficial and instrumental, the only goal being the achievement of their strategic or operational vision.
The auditors, the members of the board of directors, and the regulatory bodies play a very important role in carrying out the fraud; in fact the latter constitute the governance control mechanisms, the main role of which is prevention against any financial offense within the company [11]. What can we do about this fraudulent act? What needs to be done is great vigilance and strengthening of the following actors:
The role of the auditors is to detect anomalies, manipulate, and prevent problems and then propose solutions. Auditors are generally retained by the board of directors. The auditors are engaged to investigate and detect fraud; they diagnose the situation of the company in order to detect fraud. Fraud is the weak point of the accounting profession, and it is the responsibility of auditors to detect fraud [12]. This is why it is very important for auditors to take a dynamic approach to fraud prevention and detection. In addition, auditors must go beyond conventional fraud, which is based on detecting the rationality of fraudulent managers, characterized by a psychological profile tempted to fraud, for generally financial reasons. The act of classic financial and accounting fraud is outdated, and the new forms of fraud have changed in nature, and therefore they must be warned in advance. Thus, the fraud has to exceed the direct money gain by the fraudulent manager, to take the form of strategic decisions, with which, the fraudulent manager will generate future profits. Therefore, the auditors must also control the strategic decision-making process of the company; this imperatively passes by the elimination of the centralization of the information held exclusively by the top executives. Finally, the auditors will have to establish fraud analysis grids to also include behavioral aspects of management during meetings with their employees.
The role of the board of directors has indeed changed and has evolved in recent years, especially with acts of management fraud, which have emerged, and several practices on good governance have been introduced to better balance power within from the administration board [13]. Among these good governance practices, the following actions can be cited:
It is necessary to separate the roles between the chairman of the board of directors and the CEO.
Reduce the number of the board of directors, who hold positions within the company hold regular meetings of the board of directors, with members of management, without the presence of the CEO.
Make sure that the board can count on a roadmap and expertise in order to properly follow the actions and decisions of management.
Recruit external directors, well experienced in the field or activity of the company. During meetings of the board of directors, the following points should be raised regularly:
Update strategic action plans.
Update the succession plan.
Discuss the working atmosphere with the CEO and strengthen ties between members of the management.
The board will also have to ensure that the company works in a climate of integrity and ethics, and that its internal or external communication mechanisms are set up with the greatest transparency.
Financial analysts play almost the same roles as members of the board of directors; they must always verify the information disclosed by companies. They must analyze the financial statements well and detect any contradictions [14].
For example, fraud can appear if the analyst observed a profit which increased over a certain period, while his cash flow generated by the operation (Cash Flow) fell during the same period, this contradiction meant that there is Something is wrong [15]. In other words, if the company posted positive cumulative profits over a period, while its operation posted negative figures over the same period, this is abnormal, since as normal, growing profit, this deficit must not exist, and must be absorbed by bank loans or new equity issues.
Thus, these contradictions, or these differences between profits and cash flows, are often the sign of accounting manipulations.
Analysts will try to answer these questions:
How is it that the profit increases while the flows are negative?
How is this drain on the company’s liquidity financed?
Is there a recovery plan?
A cash budget?
Are the assets thus acquired liquid?
Are the assets good quality?
The chartered accountant is a privileged interlocutor of companies facing fraud; indeed, thanks to his skills in internal control, and his mastery of accounting procedures, his role is not negligible to fight against fraud, and notify her during her activities to her clients [5]. For the accountant, his investigative role consists in intervening within the framework of his advisory missions in the event of suspicion or fraud detected by the company. Its mission intervenes even before legal action in order to confirm or not the suspicions of fraud. In fact, its services are often requested either by the majority shareholders, or by a parent company operating with its subsidiaries, or by the company victim of a fraud committed by its senior managers.
The auditor may also be invited to investigate if there is a suspicion of customer fraud. Their investigation missions can be either audit or judicial expertise missions, and this mainly depends on the legal aspects of their missions [16]. They must carry out their missions with objectivity and professionalism while respecting the principle of professional secrecy.
The role of regulatory authorities in preventing and discovering fraud is not easy to do. Their main role is to establish the mechanisms that fight against fraud. They must manage complaints, and investigations against fraudsters, and they must ensure that the governance bodies and mechanisms of listed companies play their full role. Financial reporting must be reliable and communicated to the public on time. Establish mechanisms and apply sanctions against any natural or legal person, who tries to defraud or manipulate financial or accounting information, in order to profit personally.
The financial scandals which have appeared in recent years have placed fraud at the heart of economic and financial issues. Following this, several measures have been adopted aimed at strengthening the regulatory and legal framework such as the Sarbanes-Oxley law in the United States (July 2002) and the financial security law in France (August 2003).
At the same time, new auditing standards have been created to increase the risk of fraud being taken into account by statutory auditors: SAS 99 standards in the United States, IFA ISA 240 standard internationally transposed in France by NEP 240.
But all of this did not stop the leaders from committing the fraud. In fact, the fraud and the accounting and financial manipulations made by the senior executives of the company have affected the confidence of investors and donors toward the company and its image on the financial market.
To remedy this, financial control authorities and even government authorities have introduced a series of regulations aimed at improving corporate transparency, for example by improving the disclosure of financial information, to which companies must comply, and which they must also publish through their official documents.
The control recommendations must also relate to the risks linked to overinvestment and good governance, via better collaboration of the boards of directors with independent, external directors and above all well experienced in the field of activity of the company and especially use auditors from well-experienced accounting firms.
Cardiovascular disease is the leading cause of death in men and women in the United States and throughout the world [1]. Current efforts are focused on decreasing the burden of death due to atherosclerosis and cardiac disease overall. Increased attention has been placed on the activation of the renin-angiotensin-aldosterone system (RAAS) and pathogenetic mechanisms in cardiovascular disease. The RAAS system effects blood pressure control and electrolyte and fluid balance and therefore plays a significant role in cardiovascular hemodynamics [2, 3, 4].
Classically, it is known that angiotensinogen is cleaved by renin to form angiotensin-I (Ang I), which is then converted to angiotensin-II (Ang II) by angiotensin converting enzyme (ACE), however other peptides and products of this axis have been shown to play a role in the development of cardiovascular disease [3, 4]. It is thought that two of these products (angiotensin 1-7 and angiotensin 1-9) may have counterregulatory effects on the development of atherosclerosis and cardiovascular disease [4]. Although the role of angiotensin II is understood more clearly, these peptides provide other targets by which the RAAS system can be utilized to prevent atherosclerosis.
Overactivation or pathologic activation of the RAAS system, specifically angiotensin II, has been shown to play a specific role in endothelial dysfunction, inflammation, intense vasoconstriction, increased vascular and cardiac hypertrophy, fibrosis and the development of atherosclerosis [2, 3, 4, 5]. Multiple large investigations have shown that direct inhibition of the effects of angiotensin II via angiotensin converting enzyme inhibitors (ACE-I) and angiotensin-receptor blockers (ARB) improve mortality, prevent renal disease and decrease cardiovascular events in this subset of patients. Additionally, some studies have shown that utilization of both ARB and ACE-I may have cumulative effects on inhibiting the adverse effects of an overactivated RAAS system [6, 7].
We aim to highlight the known role of the activated RAAS and provide an updated description of the mechanisms by which overactivation of RAAS promotes disease and provide a summary of the clinical implications of RAAS inhibition in cardiovascular disease.
The RAAS system has several moving parts, with different organ systems stimulating its activation and suppression. Renin, the active form of prorenin, is secreted by the granular cells of the kidney. Although renin’s role is that of an enzyme, its means of expression are more hormonal. Renin’s production is stimulated by hypotension, hyponatremia, and decreased sympathetic activity. Renin is responsible for cleaving angiotensinogen, a protein produced in the liver. Angiotensinogen is regulated via thyroid hormone, steroids, and levels of circulating angiotensin II. Angiotensinogen is cleaved into angiotensin I, which is further converted into angiotensin II by angiotensin converting enzyme [3, 4].
RAAS key players are composed of renin, angiotensin I & II, and angiotensin converting enzyme located in the heart atria, conduction system, valves, ventricles, coronary vessels, fibroblasts and myocytes [8, 9]. Ang II is the effector hormone playing a pivotal role in the cardiac RAAS and has a widespread effect throughout the body, targeting different mechanisms of action.
Ang II acts via the angiotensin receptors mediating the following actions [9, 10]:
Cardiovascular system - vasoconstriction, increased blood pressure, increased cardiac contractility, vascular and cardiac hypertrophy
Renal system - tubular sodium reabsorption, inhibition of renin release
Sympathetic nervous system stimulation
Aldosterone synthesis through adrenal cortex
Cell growth and proliferation, inflammatory response, and oxidative stress.
Angiotensin converting enzyme 2 (ACE 2) is involved in the degradation of Ang II to Ang (1-7) and Ang (1-9), which provide a relative vasodilatory effect as outlined in Figure 1. ACE 2 is restricted to vascular endothelial cells, arterial smooth muscle cells, myofibroblasts, carotid arteries and renal tubular epithelium [8, 9, 10]. The effects of Ang II, Ang (1-7) and Ang (1-9) have been uncovered in the past several years, specifically their role in hypertension, endothelial damage, and cardiovascular disease [5, 6, 9, 12]. The role of Ang (1-7) and Ang (1-9) is further outlined in Figure 1 as they pertain to the pathophysiologic changes in the cardiovascular system.
Schematic of the RAAS as it pertains to angiotensin II and angiotensin (1-7) (Ang-(1-7)) and their counter-regulatory effects via angiotensin receptors 1 and 2 (AT1-R and AT2-R respectively) and MAS receptor (MAS) [
Endothelial dysfunction is thought to be a precursor to atherosclerosis, or the thickening and stiffness of vessels. This damage often cultivates in an atherosclerotic plaque, which is a fibrin and cholesterol contained structure that deposits on the inner lumen of blood vessels and can impede oxygen delivery to tissues and organs. Endothelial damage and inflammation allow for the migration of monocytes and macrophages to the site of injury and the formation of foam cells [13, 14, 15]. Additionally, stimulation of inflammatory mediators also promotes smooth muscle cell (SMC) thickening, stiffness of vessels and forms a fibrous cap on the atherosclerotic plaque (Figure 2) [16]. The pathophysiology of plaque development is very closely tied to RAAS as Ang II plays a key role in these pathophysiologic changes.
A schematic depicting the dynamic changes involved in the formation of an atherosclerotic plaque [
Ang II acts on the AT1 and AT2 receptors (AT1-R and AT2-R) causing arteriolar vasoconstriction, and inflammation through generation of reactive oxygen species (ROS), proinflammatory transcription factors such as nuclear factor kB (nf-kB), and the proliferation of smooth muscle cells contributing to atherogenesis [17, 18]. Activated nf-kB increases inflammatory mediators including interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1) and platelet derived growth factor (PDGF), all of which mediate inflammation, endothelial damage and monocyte migration and adhesion leading to fibrosis [6, 18].
Ang II induces NF-kappaB (NF-kB) and inflammation through its binding to AT1-R. This has been demonstrated extensively as AT1-R blockers have shown to significantly decrease inflammation. Induction of NF-kB leads to the expression of pro-inflammatory cytokines such as IL-6 and TNF-alpha [19, 20]. Additionally, IL-6 itself can activate AT1-R resulting in overexpression and production of reactive oxidative species (ROS) when RAAS is overstimulated [19]. The RAAS is also a potent oxidant stimulator, as it activates the NADH/NADPH oxidase signaling pathway, and thereby produces superoxide anions and other ROS. TNF-alpha impairs endothelial nitric oxide (NO) production in coronary arteries thereby causing vasoconstriction. Additionally, ACE plays a role in the degradation of bradykinin, which depletes NO formation as well [6, 18, 19, 20]. Overall, we have a RAAS mediated expression of ROS, inflammatory mediators, and depletion of vasodilatory NO.
This inflammation mediated cellular injury and production of ROS, activates the endothelium and increases expression of intercellular adhesion molecules (ICAM-1) and vascular cell adhesion molecules (VCAM-1), which promote endothelial damage and make cells leaky [9, 21, 22]. The endothelial damage promotes further migration of leukocytes, production of inflammatory cytokines and chemokines.
Finally, RAAS promotes thrombosis through Ang II receptors located on human platelets. Through these receptors Ang II promotes the release of thromboxane A2 and platelet derived growth factor, which promote atherosclerotic plaque formation and thrombus formation [22, 23]. Ang II involvement in endothelial dysfunction and atherosclerotic plaque formation is summarized in Figure 3.
Summarized effects of Ang II as it is known to cause endothelial damage, inflammation, migration and adhesion of monocytes, proliferation of vasculature and platelets and formation of atherosclerotic plaque and thrombus [
Hypertension, defined as a systolic blood pressure greater than 120 and diastolic pressure greater than 80, affects a quarter of the world’s population. When the etiology of hypertension is unknown, it is termed essential hypertension. When the cause of hypertension is known, by way of underlying metabolic, hormonal, neurogenic, or cardiovascular dysfunction, it is deemed as secondary hypertension [24]. As we have reviewed thus far, RAAS is responsible for maintaining sodium concentration in the blood, fluid status, and hemodynamic stability and therefore has a significant effect on blood pressure. Overactivation of RAAS can perpetuate unwanted elevations in blood pressure.
Increased levels of Ang II and subsequently aldosterone cause increases in vascular tone and hypertension. Aldosterone, a mineralocorticoid, takes its effect by binding to mineralocorticoid receptors (MR) and translocating into nucleus. Here, it integrates with cellular DNA and induces transcription of genes that regulate electrolytes and fluid balance. An over expression of aldosterone causes an elevated aldosterone-renin ratio which leads to systemic complications [4].
Patient’s with primary aldosteronism (PA) and increased aldosterone levels are at higher risk for cerebrovascular complications. Although PA is not a common diagnosis, fifteen percent of patients with essential hypertension have higher than normal levels of circulating aldosterone. We can conclude that this sub-set of essential hypertension patients will have similar end-organ effects of elevated aldosterone as do patients with PA [4].
Hypertension itself can cause endovascular injury, which leads to increased production of ROS and inflammatory mediators ultimately contributing to atherosclerosis [25, 26]. The result of such endothelial injury is worsening cardiovascular disease, hypertension, and renal dysfunction. We see this manifest in the kidney with proteinuria and collagen deposition. Eventually, healthy kidney parenchyma is replaced with fibrotic tissue, leading to even more dysregulation with blood pressure homeostasis. In the cardiovascular system, inflammatory damage from overactivation of RAAS and hypertension causes calcifications and fibrosis. As such, inhibition of the RAAS system with ACE-I and ARB has become a cornerstone in therapy for hypertensive patients, particularly those with evidence of diabetes, microalbuminuria and in CAD patients overall [15, 25, 26, 27, 28]. The details of some of the landmark clinical trials contributing to the guidelines in treatment with ACE-I and ARB are further discussed in this chapter.
Coronary artery disease (CAD) or Ischemic heart disease (IHD), develops when there is a limitation of blood flow within the coronaries. It occurs due to the gradual buildup of atherosclerotic plaque within the wall of arteries leading to reduced oxygen delivery to cardiac myocytes. It comprises a clinical spectrum based on the degree of luminal narrowing and the activation of the atherosclerotic plaque [13, 14]. The RAAS plays a vital role in the pathogenesis of CAD. Evidence supports that RAAS controls atherosclerosis through intracellular signaling pathways by mediating endothelial function, inflammation, fibrinolytic balance, growth, lipid-glucose metabolism, and its vasoconstrictor function.
Ang II has growth promoting effects by regulating growth of vascular smooth muscle cells and activating the growth associated kinase pathways. In states of ischemia, there is increased vascular endothelial growth factor (VEGF) expression. In vascular smooth muscle cells, transforming growth factor B1, platelet derived growth factor causes fibrosis and cellular hypertrophy. These angiogenic factors lead to the formation of new cells, fibrin, and collagen deposition leading to growth of the plaque and thickening of vessels [20, 21].
RAAS plays a role in altering the fibrinolytic balance as well by inhibiting fibrinolysis and enhancing thrombosis. Within the vessels, Ang II stimulates the release of plasminogen activator inhibitor - I (PAI-I) thereby reducing the fibrinolytic activity. It activates tissue factor which acts as a cofactor for factor VII, potentiating the coagulation cascade [22, 23]. The above mechanism increases the thrombogenic activity.
Ang II overexpression causes endothelial inflammation and activation of cytokine cascade thereby causing progression of atherosclerotic plaque. The silent plaque ruptures when the inflammation overwhelms the stable fibrous cap causing thrombosis and acute ischemia [13, 14].
Heart failure is a clinical syndrome categorized based on clinical signs and symptoms and further subclassified by echocardiography findings. As per the American College of Cardiology, left ventricular ejection fraction (LVEF) of ≥50% is defined as heart failure with preserved ejection fraction (HFpEF), LVEF 41-49% as heart failure with mid-range ejection fraction (HFmrEF), LVEF≤40% as heart failure with reduced ejection fraction (HFrEF). HFrEF particularly occurs after an inciting event like myocardial injury, arrhythmias, cardiomyopathies, substance abuse, infections or genetic diseases which put the heart in a state of stress leading to contractile dysfunction and cellular remodeling [29]. The circulatory changes arising from heart failure are sensed by the peripheral baroreceptors and chemoreceptors, thereby activating a sequalae of compensatory neurohormonal mechanisms. The compensatory mechanisms include activation of sympathetic nervous system (SNS) and RAAS. RAAS plays an integral role in cardiac contractility, homeostatic control of blood pressure and electrolyte-fluid balance [30, 31].
In an adult with normal circulation, the baroreceptors located in the carotid sinus and aortic arch balance the sympathetic and parasympathetic outflow from the central nervous system. Alterations in the cardiac output change the effective arterial blood volume resulting in inhibition of parasympathetic response and a reflux increase in the sympathetic vascular tone. The increased sympathetic activity leads to vasoconstriction of the renal afferent arteriole and decreases blood flow to the kidney [29, 32]. This activates renin secretion and thereby RAAS.
Renin is secreted in response to 4 main stimuli [10, 33]:
Decreased renal perfusion pressure sensed by baroreceptor cells in the arterial vessel wall
Decreased intracellular chloride levels (altered NaCl delivery)
Sympathetic nerve stimulation via beta-1 adrenergic receptors
Negative feedback by a direct action of Ang II
The pathophysiology of heart failure allows for decreased renal perfusion and increased sympathetic response, both of which cause an overactivation of the RAAS [34]. The overstimulation of RAAS in heart failure is further depicted in Figure 4.
The regulatory effects of RAAS as it pertains to heart failure mechanics [
In pathological states like pressure or volume overload, cardiac tissues exhibit elevated levels of renin and Ang II levels leading to cardiac hypertrophy, myocardial fibrosis, hypertensive heart disease and chronic heart failure through mechanics explained earlier. Additionally, post-infarction levels of ACE-2 have been shown to be elevated, which may explain a counter-regulatory mechanism to protect against the Ang-II mediated myocardial damage. When this natural counter-regulatory mechanism is lost in ACE-2 knockout animal models the levels of dilated cardiomyopathy were much more pronounced. Several trials have also looked at specific levels of plasma renin and HFrEF and have found that those with elevated levels had an associated worse outcome than their counterparts. In patients with advanced heart failure, baseline levels of plasma renin and plasma aldosterone are persistently high, which further exemplifies the role of RAAS in cardiac remodeling and heart failure [35, 36, 37].
Innovative studies have discovered that a particular breakdown product of Ang 1-7, also known as Alamandine, has shown to prevent ventricular and vascular remodeling in animal models [11]. Studies of by-products offer areas of potential research as we grow to understand the intricacies of the molecular pathways that play a role in the development of heart failure.
The overactivation of RAAS and its effects on the pathophysiology of hypertension, vascular stiffness, ischemia, thrombosis, and left ventricular (LV) remodeling has been well documented. As such, several medications that impede the harmful effects of the overactivation of RAAS have been shown to prevent the negative clinical outcomes. Here we review some of the landmark clinical trials that have contributed to the current guidelines and recommendations for the treatment of hypertension, ischemic heart disease and heart failure (Table 1).
Trial Name (Date) | Primary/ Secondary Outcomes | Inclusion Criteria | Intervention | Number of Patients /Follow-up Time | Results |
---|---|---|---|---|---|
Rate of eGFR change, progression of CKD or all-cause mortality | AA, Age 18-70, DBP >95 mmHg, HTN renal Disease, eGFR 20-65 | BP control – with ramipril, amlodipine or metoprolol | 1,094/4 years | No difference in progression of CKD. Use of ACE-I associated with fewer CKD events or death | |
6 Month Mortality | NYHA IV HFrEF, optimal treatment with at least diuretic and digitalis or other medications (nitrates, prazosin, hydralazine) | Enalapril VS placebo | 253/6-20 months (about 1 and a half years) | Six-month mortality with enalapril was 26% as opposed to 44% with placebo | |
All-cause mortality, CV death, Death due to MI, Death due to stroke | HF, LVEF <35%, Receiving conventional therapy without ACE-I | Enalapril VS placebo | 2,569/3.5 years | Enalapril reduces 4-year mortality by 16% and reduces HF hospitalizations | |
2-year mortality, hemodynamic effects, EF, exercise tolerance, adherence | Men ages 18-75, reduced exercise tolerance, cardiac dysfunction, receiving optimal and stable therapy | Enalapril. VS ISDN/ hydralazine | 804 men/2.5 years | Enalapril improved survival compared to combination of ISDN and hydralazine | |
All-cause mortality | Age over 21 years, MI in prior 3 days, new onset LVEF less than 40%, absence of overt signs of CHF | Captopril VS placebo | 2,231/42 months (about 3 and a half years) | In patients with acute MI complicated by low EF, captopril led to 19% reduction in all-cause mortality | |
All-cause mortality | Age > 18 years, Acute MI within prior 10 days complicated by HF, LVEF <35% on echocardiogram or < 40% on radionucleotide ventriculography | Valsartan VS valsartan + captopril VS captopril | 14,703/ 24 months (about 2 years) | Valsartan was as effective as captopril in improving survival | |
All-cause mortality | 50 years of age or older with confirmed acute MI and HF in acute phase or a new Q-wave anterior infarction or reinfarction | Losartan VS captopril | 5,477/2.7 years | No significant change in mortality between the two drugs, however losartan was better tolerated | |
Cardiovascular death or HF admission | LVEF>40%, NYHA class II-IV symptoms for at least 4 weeks, history of at least one cardiac hospitalization | Candesartan VS placebo | 3,020/3 years | Candesartan modestly reduced the rate of HF-related hospitalizations. No effect on CV mortality | |
Death from any cause, hospitalization for CV disease | 40 years of age or older and had NYHA class II-IV and an EF of at least 45% | Irbesartan VS placebo | 4,128/49 months | Irbesartan did not improve mortality in patients with HFpEF | |
CV mortality or HF hospitalizations | Age > 18 years, LVEF<40% in prior 6 months, NYHA II-IV, treatment with stable ACE-I dose for >30 days | Candesartan VS placebo | 2,548/ 41 months | Addition of candesartan reduced CV mortality of HF hospitalization | |
All-cause mortality, cardiac arrest with resuscitation, HF hospitalization | Age > 18 years, NYHA II-IV, receipt of a fixed dose of medical therapy (ACE, digoxin, diuretics, and/or BB) for >2 weeks, EF < 40% | Valsartan VS placebo | 5,010/23 months (about 2 years) | In a time where HF management included ACE but not BB, addition of ARB decreased HF hospitalizations | |
CV mortality, MI, stroke, HF hospitalization | Age over 55 years with CAD, PAD, CV disease or high-risk DM | Telmisartan VS Ramipril VS Telmisartan and Ramipril | 25,620/56 months (about 4 and a half years) | Patients with CV disease or DM with complications telmisartan was as good as Ramipril in preventing death, MI, and stroke. The combination of both however had no increase in benefit and was associated with more adverse events. | |
All-cause mortality | NYHA IV within 6 months to enrollment, NYHA III or IV at the time of enrolment, treatment with ACE and a loop diuretic, LVEF <35% | Spironolactone VS placebo | 1,663/2 years | Spironolactone led to 30% reduction in all-cause mortality without significant side-effects | |
CV mortality, aborted cardiac arrest, or HF hospitalization | Age > 50 years, LVEF >45%, SBP <140 or < 160 if on 3 anti-hypertensives, serum potassium <5, elevated BNP in last 60 days, or HF hospitalization in last 12 months | Spironolactone VS placebo | 3,445/3 years | Spironolactone did not reduce CV mortality however did result in a small reduction in HF hospitalizations | |
CV death or hospitalization, all-cause mortality, fatal or non-fatal MI | Age > 55 years, NYHA II, EF < 30%, treatment with ACE, ARB or both, treatment with BB, CV hospitalization in last 6 months | Eplerenone VS placebo | 2,737/21 months (about 2 years) | Eplerenone reduces the risk of death and hospitalization in patients with low EF and NYHA II | |
CV mortality or HF hospitalization | Age > 18 years, NYHA class II-IV, EF <35%, if no HF hospitalizations in last year BNP >150 pg./mL, ACE, or ARB and BB with stable dose, If HF hospitalization in last year BNP >100 pg./mL | ARNI VS enalapril | 8,399/27 months (about 2 and a half years) | ARNI reduces CV mortality or HF hospitalizations when compared to enalapril. Also reduces all-cause mortality | |
HF hospitalizations and CV mortality, change in NYHA class at 8 months, all-cause mortality | >50 years of age, LVEF>45%, NYHA II-IV, and at least one of the following: HF hospitalization with NT-proBNP>200 (no AFIB) or > 600 (AFIB) or NT-proBNP>300 (no AFIB) or > 900 (Afib) on screening visit ECG | ARNI VS valsartan alone | 4,822/35 months (about 3 years) | ARNI did not lower hospitalizations or death from CV causes, however there was a modest improvement in NYHA class and a slower decline in renal function than what was seen in valsartan alone | |
Time-averaged change in NT-proBNP concentration from baseline through weeks 4-8 | Age > 18 years, LVEF<40%, NT-proBNP of 1600 pg./mL or more, or BNP of 400 pg./mL or more, receiving diagnosis of acute decompensated HF up to10 days after presentation | ARNI versus enalapril | 881/2 years | ARNI decreased NT-proBNP compared to enalapril therapy without significant change in rate of adverse events | |
Death from CV causes, nonfatal MI, nonfatal stroke, ESRD, death attributable to kidney failure, or the need for RRT | 35 years or older with type 2 diabetes and evidence of microalbuminuria, macroalbuminuria, or cardiovascular disease | Aliskiren VS placebo | 8,561/32 months (about 2 and a half years) | The addition of aliskiren to standard therapy in patients with type 2 diabetes who are at elevated risk for CV and renal events is potentially harmful |
Trials documenting improvement in cardiovascular outcomes and reduced cardiovascular mortality with renin-angiotensin-aldosterone system inhibition.
Summarized landmark clinical trials depicting the benefits of RAAS inhibition in cardiac and renal patients.
In the treatment of hypertension, the patient’s specific co-morbidities must be considered prior to initiating therapy including, race, diabetes, kidney function and other high-risk pre-existing conditions that may predispose to CV outcomes. One landmark trial, the AASK trial (2002), studied African Americans with hypertension and kidney disease and compared intensive blood pressure control versus conservative blood pressure control with ACE-I, metoprolol, and amlodipine. The two groups had no difference in the progression to CKD, however patients on ACE-I had less chronic kidney disease events and death, which solidified the use of ACE-I in patients with CKD [38].
The mainstay of treatment in patients with heart failure and CAD is blockade of the RAAS. Multiple trials highlighted in Table 1 have been performed showing improvement in cardiovascular (CV) outcomes and reduced CV mortality.
The first trial to demonstrate improved CV outcomes with HFrEF is the CONSENSUS (1987) trial conducted among New York Heart Association (NYHA) Class IV HF and cardiomegaly patients which compared enalapril and placebo. Six-month mortality with enalapril was 26% as opposed to 44% with placebo [39]. The SOLVD (1991) treatment trial chose patients with HF and LVEF ≤35%, NYHA II-IV, with similar randomization, showing mortality reduction by 16% due to reduction of death in patients on enalapril versus placebo. This study also showed a decrease in CV related hospitalizations [40]. Further research with the V-HeFT II (1991) trial showed that ACE-I was superior in improving survival to vasodilators such as isosorbide dinitrate and hydralazine [41]. Additionally, use of ACE-I as a disease modifying drug was established post-MI in the SAVE trial (1992), which is further discussed in Table 1 [42].
Additional studies looked to compare the effects of ACE-I versus ARB. These trials were the VALIANT (2003) trial and the OPTIMAAL (2002) trial. The VALIANT trial showed that valsartan was as effective as captopril in improving survival among patients with HF and/or LV disfunction in the post-MI period [43]. The OPTIMAAL trial compared losartan and captopril in high-risk patients after acute myocardial infarction with LV-dysfunction and heart failure and found no difference in mortality outcomes [44]. Similar studies in patients with HFpEF were conducted, including the CHARM-Preserved trial (2003) and the I-PRESERVE trial (2008). CHARM- Preserved showed that candesartan modestly reduced HF-related hospitalizations however had no effect on mortality [45]. I-PRESERVE used Irbesartan in HFpEF patients and similarly found no reduction in mortality [46].
The thought that the addition of an ARB to an ACE inhibitor could inhibit RAAS more significantly was established. This was compared in two large significant trials. The CHARM-added trial compared symptomatic HF patients with LVEF ≤40% who were already on an ACE inhibitor with either addition of candesartan or placebo. This trial showed a reduction in CV mortality and HF hospitalizations; however, it was accompanied by a significant increase in hyperkalemic events [47]. The Val-HeFT (2001) compared patients with symptomatic HF, LVEF <40% with LV dilatation and on ACE inhibitors by adding either valsartan or placebo. There was no effect on mortality however, there was a 23% reduction in HF hospitalization in the treatment group [48]. Finally, the ONTARGET trial (2008) compared ramipril to telmisartan to a combination of both in patients with CV disease or diabetes with complications and found that the combination of telmisartan plus ramipril had no increase in benefit and was associated with more adverse events [49].
Several trials looking at the effects of aldosterone antagonists and heart failure patients were conducted with overall favorable results. Patients benefit from reduced sympathetic stimulation and alleviate fluid overload from sodium and water retention through aldosterone blockade. The RALES trial (1999) studied the role of spironolactone in patients with LVEF≤35% and NYHA class III-IV, which showed that Spironolactone, along with ACE-I (as most patients were already on ACE-I) showed a 11% reduction in CV mortality compared to placebo [50]. The TOPCAT trial (2014) done in patients with HFpEF and controlled blood pressures to receive spironolactone or placebo. This study conversely showed that spironolactone did not reduce CV mortality however did result in a small reduction in HF hospitalizations [51]. Another trial, the EMPHASIS-HF trial (2011), looked at Eplerenone versus placebo in HF patients, NYHA class II, showed that Eplerenone reduced the risk of death and hospitalizations in patients with HF [52].
A newer group of RAAS inhibition medications combining an ARB and neprilysin inhibitor (ARNI) was studied in 2014 in the PARADIGM-HF trial. Neprilysins are key enzymes in the degradation of natriuretic peptides. They increase endogenous natriuretic peptide levels including bradykinin, thereby promoting vasodilation and natriuresis. Neprilysins were initially attempted with an ACE inhibitor combination however this led to incidences of angioedema given increased levels of bradykinin. PARADIGM - HF trial was conducted in patients with symptomatic HF and LVEF ≤40% assigned to enalapril alone or valsartan-sacubitril combination. This showed significant reduction in CV mortality, all-cause mortality, and HF hospitalizations with no increase in angioedema events [53]. The PARAGON-HF trial (2019) studied ARNI versus valsartan alone in HFpEF patients with EF > 45% and NYHA II to IV and showed that ARNI did not lower hospitalizations or death from CV causes, however there was a modest improvement in NYHA class and a slower decline in renal function than what was seen in valsartan alone [54]. The PIONEER-HF trial (2019) showed that initiated of ARNI versus enalapril in acute diastolic heart failure patients allowed for significant reductions in HF biomarker, NT-proBNP, without significant change in adverse effects [55].
Direct renin inhibitors have been attempted with the goal of reducing renin and thereby the entire RAAS cascade. The ALTITUDE trial (2012) added aliskiren to patients with diabetes type 2 in order to prevent kidney disease and CV outcomes. These patients were on ACE-I however the addition of aliskiren led to an increase in CV mortality, hypotension, and adverse hyperkalemic events. The trial was stopped early due to higher mortality findings [56].
RAAS is a complex and evolving pathway that has been implicated in the pathogenesis of endothelial damage, atherosclerosis, and cardiac remodeling. Inhibition of the negative effects of overactivated RAAS has shown to cause morbidity and mortality benefits in cardiovascular disease outcomes. Significant research has yet to be performed on the possibility of stimulating the counter-regulatory effects of RAAS through AT2-R and MAS-R. Such mechanisms are still being studied in animal models; however, the effects of AT2-R and MAS-R offer potential areas of continued research and potential targets for future therapy.
No conflicts of interest exist for this work by any of the authors.
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His studies in robotics lead him not only to a PhD degree but also inspired him to co-found and build the International Journal of Advanced Robotic Systems - world's first Open Access journal in the field of robotics.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"441",title:"Ph.D.",name:"Jaekyu",middleName:null,surname:"Park",slug:"jaekyu-park",fullName:"Jaekyu Park",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/441/images/1881_n.jpg",biography:null,institutionString:null,institution:{name:"LG Corporation (South Korea)",country:{name:"Korea, South"}}},{id:"465",title:"Dr",name:"Christian",middleName:null,surname:"Martens",slug:"christian-martens",fullName:"Christian Martens",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"479",title:"Dr.",name:"Valentina",middleName:null,surname:"Colla",slug:"valentina-colla",fullName:"Valentina Colla",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/479/images/358_n.jpg",biography:null,institutionString:null,institution:{name:"Sant'Anna School of Advanced Studies",country:{name:"Italy"}}},{id:"494",title:"PhD",name:"Loris",middleName:null,surname:"Nanni",slug:"loris-nanni",fullName:"Loris Nanni",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/494/images/system/494.jpg",biography:"Loris Nanni received his Master Degree cum laude on June-2002 from the University of Bologna, and the April 26th 2006 he received his Ph.D. in Computer Engineering at DEIS, University of Bologna. 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He is currently a principal researcher in data analytics and optimisation at TECNALIA (Spain), a visiting fellow at the Basque Center for Applied Mathematics (BCAM) and a part-time lecturer at the University of the Basque Country (UPV/EHU). His research interests gravitate on the use of descriptive, prescriptive and predictive algorithms for data mining and optimization in a diverse range of application fields such as Energy, Transport, Telecommunications, Health and Industry, among others. In these fields he has published more than 240 articles, co-supervised 8 Ph.D. theses, edited 6 books, coauthored 7 patents and participated/led more than 40 research projects. 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Initial biochemical studies have been exclusively analytic: dissecting, purifying, and examining individual components of a biological system; in the apt words of Efraim Racker (1913 –1991), “Don’t waste clean thinking on dirty enzymes.” Today, however, biochemistry is becoming more agglomerative and comprehensive, setting out to integrate and describe entirely particular biological systems. The ‘big data’ metabolomics can define the complement of small molecules, e.g., in a soil or biofilm sample; proteomics can distinguish all the comprising proteins, e.g., serum; metagenomics can identify all the genes in a complex environment, e.g., the bovine rumen. 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Thus proteomics, an area of research that detects all protein forms expressed in an organism, including splice isoforms and post-translational modifications, is more suitable than genomics for a comprehensive understanding of the biochemical processes that govern life. The most common proteomics applications are currently in the clinical field for the identification, in a variety of biological matrices, of biomarkers for diagnosis and therapeutic intervention of disorders. From the comparison of proteomic profiles of control and disease or different physiological states, which may emerge, changes in protein expression can provide new insights into the roles played by some proteins in human pathologies. Understanding how proteins function and interact with each other is another goal of proteomics that makes this approach even more intriguing. Specialized technology and expertise are required to assess the proteome of any biological sample. Currently, proteomics relies mainly on mass spectrometry (MS) combined with electrophoretic (1 or 2-DE-MS) and/or chromatographic techniques (LC-MS/MS). MS is an excellent tool that has gained popularity in proteomics because of its ability to gather a complex body of information such as cataloging protein expression, identifying protein modification sites, and defining protein interactions. 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