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Renin-angiotensin-aldosterone system blockade for cardiovascular diseases: Current status
British Journal of Pharmacology
Abstract
Activation of the renin-angiotensin-aldosterone system (RAAS) results in vasoconstriction, muscular (vascular and cardiac) hypertrophy and fibrosis. Established arterial stiffness and cardiac dysfunction are key factors contributing to subsequent cardiovascular and renal complications. Blockade of RAAS has been shown to be beneficial in patients with hypertension, acute myocardial infarction, chronic systolic heart failure, stroke and diabetic renal disease. An aggressive approach for more extensive RAAS blockade with combination of two commonly used RAAS blockers [ACE inhibitors (ACEIs) and angiotensin receptor blockers (ARBs)] yielded conflicting results in different patient populations. Combination therapy is also associated with more side effects, in particular hypotension, hyperkalaemia and renal impairment. Recently published ONTARGET study showed ACEI/ARB combination therapy was associated with more adverse effects without any increase in benefit. The Canadian Hypertension Education Program responded with a new warning: 'Do not use ACEI and ARB in combination'. However, the European Society of Cardiology in their updated heart failure treatment guidelines still recommended ACEI/ARB combo as a viable option. This apparent inconsistency among guidelines generates debate as to which approach of RAAS inhibition is the best. The current paper reviews the latest evidence of isolated ACEI or ARB use and their combination in cardiovascular diseases, and makes recommendations for their prescriptions in specific patient populations.
... 6,7 Furthermore, both drugs are widely used for various indications, particularly in cardiovascular diseases. 8,9 Therefore, guidance on the use of these drugs in COVID-19 patients is sorely needed. In this review, we explain the interaction of SARS-CoV2 and ACE, the benefit of continuing vs. harm of discontinuing of RAAS blockers, and we presented summaries of recommendations from various societies and colleges around the world regarding the use of ACEi/ARB in COVID-19 patients. ...
... 12,13 ACE2 shares considerable homology to ACE, but unlike ACE, it does not convert angiotensin I (Ang I) to angiotensin II (Ang II). ACE2 degrades angiotensin I to angiotensin- (1)(2)(3)(4)(5)(6)(7)(8)(9) and angiotensin II to angiotensin-(1-7). 12,14 The renin-angiotensin-aldosterone system (RAAS) is a critical regulator of blood volume and systemic vascular resistance. ...
With a rapidly growing pandemic of coronavirus disease of 2019 (COVID-19), a public health emergency of international concern, the medical communities and national health systems are being tested for their preparedness. The culprit that is responsible for this viral respiratory disease, is a novel type of coronavirus, now identified as severe acute respiratory syndrome coronavirus - 2 (SARS-CoV2). At the present time, there are gaps in the knowledge regarding the safety of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) for COVID-19 patients due to concern of ACE2, which is critical for viral entry and their levels are upregulated when using these (Renin Angiotensin Aldosterone System) RAAS blockers. ACE2 is a glycoprotein metalloprotease that plays an essential role in physiologic and pathological states and it is ubiquitously found in human organs. Despite sharing homology, ACE is different from ACE2, and while the former cleaves angiotensin 1 to angiotensin 2, the latter cleaves angiotensin two to angiotensin 1-7. Extrapolated from experimental animal studies, ACE2 and angiotensin 1-7 are important and protective for the lung physiology based on mice model of acute lung injury by various causes. Other evidence also demonstrates harm over benefits when stopping RAAS blockers, particularly in patients with cardiovascular disease, in which using these drugs are proven to be life-saving. In the light of the paucity of evidence derived from well-designed study, societies and colleges recommend continuing RAAS blockers until new evidence says otherwise.
... Hypertension has been considered the main risk factor for CDs in the world [230]. The renin activates phospholipase A2 which controls blood pressure [231]. ...
Polyphenols, a wide group of secondary metabolites found in plants and some
animals too, have gained significant attention in recent years due to their
outstanding bioactivity and potential therapeutic applications. This chapter will
provide a brief overview of the bioactivity of polyphenols, highlighting their
importance in the treatment of different disorders. Polyphenols exhibit strong
anticancer properties, demonstrated through multiple in vitro and in vivo studies.
Their potential to inhibit cancer growth, progression, metastasis, induction of
apoptosis, and modulation of multiple signaling pathways involved in cancer make
them effective candidates for the treatment of cancer. Furthermore, polyphenols
have significant antibacterial action, by disrupting cell membranes and inhibiting
the synthesis of different enzymes, making them valuable agents for overcoming
bacterial drug resistance. Moreover, they also possess antiaging properties,
attributed to their strong antioxidant potential. They assist in combating cellular
damage and reducing the aging process by lowering oxidative stress and
scavenging free radicals. In addition to all this, polyphenols exert antidiabetic effects
by modulating the metabolism of glucose, increasing the sensitivity of insulin, and
lowering oxidative stress, offering potential therapeutic benefits for being effective
against diabetes mellitus. Polyphenols also show cardioprotective effects, with
evidence describing their potential to improve cardiovascular health by lowering
inflammation, blood pressure, and free radicals, and inhibiting aggregation of
platelets. Furthermore, recent studies also highlight antiviral, anti-Alzheimer,
antifungal, and antiparasitic activities. In conclusion, the abundance of literature
overwhelmingly demonstrates the bioactivity of polyphenols against various
diseases. Understanding the primary mechanisms behind the bioactivity of
polyphenols holds great promise for developing innovative therapeutic interventions
for different disease conditions.
... Renin converts the hepatic-derived angiotensinogen to angiotensin-I (AT-I), the rate-limiting reaction of the series. Angiotensin-converting enzyme (ACE), a metalloprotease primarily produced by the lungs, then cleaves AT-I to its active form angiotensin-II (AT-II), which then exerts a myriad of biological actions in the body (124). In addition to this systemic pathway, several studies have substantiated the presence of the local Renin-Angiotensin System (RAS) that operates through autocrine/paracrine mechanisms rather than the endocrine pathway (125). ...
Endocrine modulation of various growth and survival mechanisms is at the helm of cellular homeostasis and impaired endocrine balance may potentially galvanize cardiovascular health to go haywire. Melatonin, an effective antioxidant and multipotent hormone has preponderant influence on the activities of several endocrine factors including growth hormones, thyroid hormones, gastro-intestinal hormones, and those controlling reproductive and metabolic functions. Many of these hormones tightly regulate cardiovascular functions while the mammalian heart has its own endocrine machinery. Endocrine disruptions severely affect cardiovascular integrity and hormonal therapies may instigate adverse cardiac events. Therefore, this review focuses on the cardioprotective potential of melatonin concerning endocrine instability-mediated cardiovascular dysfunction. Melatonin has been reported to effectively counteract sympathetic overstimulation and also reduce the cardiotoxic attributes of catecholamines and their derivatives. Melatonin suppresses the pernicious cardiovascular manifestation of thyrotoxicosis and autoimmune thyroiditis, which is possibly attributed to its antioxidant property and regulation of iodothyronine-deiodinase activity. Interestingly, being a circadian synchronizer melatonin potentially preserves the diurnal pattern of insulin secretion and thereby improves glucose tolerance and cardiac GLUT-4 expression. Besides, melatonin modulates insulin signaling pathway by enhancing the activation of insulin receptor-associated tyrosine kinase, thus protecting the heart against diabetogenic outcomes. Further, melatonin has demonstrated its beneficial action against non-dipper hypertension by regulating the RAAS function. However, there is a plethora of unresolved research question that necessitates additional investigation into the potential therapeutic effect of melatonin in endocrine dysfunctions that emanates during various physiological and pathological states and may have potentially harmful cardiovascular implications.
... Hyperglycemia-induced podocyte injury in DKD has been previously modeled using the local renin-angiotensin system in renal podocyte cells [18]. It is well known that dysregulation of the renin-angiotensin-aldosterone system is a phenomenon implicated in the pathophysiology of both renal disorders [6] and cardiovascular disorders, such as hypertension and congestive heart failure [21]. ...
Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease worldwide. This study’s goal was to identify the signaling drivers and pathways that modulate glomerular endothelial dysfunction in DKD via artificial intelligence-enabled literature-based discovery. Cross-domain text mining of 33+ million PubMed articles was performed with SemNet 2.0 to identify and rank multi-scalar and multi-factorial pathophysiological concepts related to DKD. A set of identified relevant genes and proteins that regulate different pathological events associated with DKD were analyzed and ranked using normalized mean HeteSim scores. High-ranking genes and proteins intersected three domains—DKD, the immune response, and glomerular endothelial cells. The top 10% of ranked concepts were mapped to the following biological functions: angiogenesis, apoptotic processes, cell adhesion, chemotaxis, growth factor signaling, vascular permeability, the nitric oxide response, oxidative stress, the cytokine response, macrophage signaling, NFκB factor activity, the TLR pathway, glucose metabolism, the inflammatory response, the ERK/MAPK signaling response, the JAK/STAT pathway, the T-cell-mediated response, the WNT/β-catenin pathway, the renin–angiotensin system, and NADPH oxidase activity. High-ranking genes and proteins were used to generate a protein–protein interaction network. The study results prioritized interactions or molecules involved in dysregulated signaling in DKD, which can be further assessed through biochemical network models or experiments.
... 61 However, inhibition of the RAS has also been linked to cardioprotective effects, exemplifying the complexity of the disease. 62,63 In a recent study, 13 the source of AGT and its effect on cardiac function in acute sepsis has been determined using the cecal ligation mouse model. Plasma AGT concentrations were increased in mice with sepsis-induced myocardial dysfunction, accompanied by increased AGT protein in the liver and heart. ...
AGT (angiotensinogen) is the unique precursor for the generation of all the peptides of the renin-angiotensin system, but it has received relatively scant attention compared to many other renin-angiotensin system components. Focus on AGT has increased recently, particularly with the evolution of drugs to target the synthesis of the protein. AGT is a noninhibitory serpin that has several conserved domains in addition to the angiotensin II sequences at the N terminus. Increased study is needed on the structure-function relationship to resolve many unknowns regarding AGT metabolism. Constitutive whole-body genetic deletion of Agt in mice leads to multiple developmental defects creating a challenge to use these mice for mechanistic studies. This has been overcome by creating Agt -floxed mice to enable the development of cell-specific deficiencies that have provided considerable insight into a range of cardiovascular and associated diseases. This has been augmented by the recent development of pharmacological approaches targeting hepatocytes in humans to promote protracted inhibition of AGT synthesis. Genetic deletion or pharmacological inhibition of Agt has been demonstrated to be beneficial in a spectrum of diseases experimentally, including hypertension, atherosclerosis, aortic and superior mesenteric artery aneurysms, myocardial dysfunction, and hepatic steatosis. This review summarizes the findings of recent studies utilizing AGT manipulation as a therapeutic approach.
... For perspective, SOD-2 is one of the essential antioxidant enzymes that protect against elevated reactive oxygen species (ROS) in diverse organs and the vascular system, while eNOS plays a fundamental role in the vasorelaxation and modulation of involved in atherogenesis [21,98]. ACE, on the other hand, and as discussed earlier, plays a very important role in vasoconstriction by catalyzing the conversion of angiotensin I to angiotensin II [99][100][101]. ...
While the cardiovascular effects of Kolaviron (KV) and Garcinia kola (GK) are documented in the literature, a thorough search through literature revealed a fragmentation of information on the effect of KV and GK on cardiovascular diseases (CVDs). This systematic review aims to evaluate and summarize preclinical or clinical evidence on the effect of KV and GK on CVDs. Using the PRISMA guidelines, a systematic literature search was conducted in five medical databases (PubMed, Cochrane, EMBASE, CINAHL, and Web of Science). Inclusion criteria included both in vivo and in vitro studies related to CVDs. Eligible studies included those in which specific clinical parameters, CVD biomarkers, or voltage-gated channel effects were reported. The quality of the included studies was assessed using a modified Collaborative Approach to Meta-Analysis and Review of Animal Data from the Experimental Studies (CAMARADE) checklist. A total of 22 studies were included in this systematic review. The median and mean values of the included studies' quality scores were 6 and 5.864 ± 0.296, respectively. The results from the quality assessment of included studies validate their suitability, usefulness, and fit. Based on this systematic review, the effect of KV and GK on CVDs can be divided into eight emerging trends: (1) Anti-hypertensive/Blood pressure lowering effect; (2) Lipid profile improvement effect (3) Anti-atherosclerotic effect; (4) Anti-thrombotic effect; (5) Cardioprotection; (6) Vasodilatory effect; (7) Antioxidant effects; and (8) Genetic expression and therapeutic target for cardiovascular dysfunction. From this systematic review, it can be concluded that KV is helpful in managing CVD risk factors such as hypertension and high lipids/cholesterol. Several included studies in this review demonstrated the antihypertensive, lipid improvement, antioxidant, and signaling pathway modulation effects of KV. This potentially makes KV a good therapeutic target for the management of CVDs.
... Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are primary inhibitors of RAAS [50]. These RAAS inhibitors are recommended for patients with cardiovascular disease, diabetes and renal failure [51]. SARS-CoV-2 enters the cells of the lower respiratory tract of infected patients using membrane-bound protein ACE2 receptor ( Figure 1). ...
... In this intricate arrangement, the vasoconstrictive attributes of catecholamines, cortisol and angiotensin II (Kanaide et al., 2003;Riad et al., 2002;Ullian, 1999), work in harmony to complement AVP's actions in not only constricting blood vessels, but also enhancing water retention (Cuzzo et al., 2023) thus contributing to the maintenance of blood volume and pressure during instances of heightened sympathetic activity while adjusting to changing physiological demands (Fig. 3). In certain pathological conditions, such as heart failure, kidney dysfunction, or chronic hypertension, the AVP system and the RAAS may become disintegrated reflected in excessive water retention, electrolyte imbalances, and increased blood pressure (Ames et al., 2019;Ma et al., 2022;Ma et al., 2010). ...
... The Renin-Angiotensin-Aldosterone System (RAAS) is a key player in blood pressure regulation. In CKD, the kidneys' diminished ability to filter blood triggers the release of renin [57]. This initiates a cascade resulting in the production of angiotensin II and aldosterone. ...
Chronic kidney disease (CKD) poses a global health challenge, engendering various physiological and metabolic shifts that significantly impact health and escalate the susceptibility to severe illnesses. This comprehensive review delves into the intricate complexities of CKD, scrutinizing its influence on cellular growth homeostasis, hormonal equilibrium, wasting, malnutrition, and its interconnectedness with inflammation, oxidative stress, and cardiovascular diseases. Exploring the genetic, birth-related, and comorbidity factors associated with CKD, alongside considerations of metabolic disturbances, anemia, and malnutrition, the review elucidates how CKD orchestrates cellular growth control. A pivotal focus lies on the nexus between CKD and insulin resistance, where debates persist regarding its chronological relationship with impaired kidney function. The prevalence of insulin abnormalities in CKD is emphasized, contributing to glucose intolerance and raising questions about its role as a precursor or consequence. Moreover, the review sheds light on disruptions in the growth hormone and insulin-like growth factor axis in CKD, underscoring the heightened vulnerability to illness and mortality in cases of severe growth retardation. Wasting, a prevalent concern affecting up to 75% of end-stage renal disease (ESRD) patients, is analyzed, elucidating the manifestations of cachexia and its impact on appetite, energy expenditure, and protein reserves. Taste disturbances in CKD, affecting sour, umami, and salty tastes, are explored for their implications on food palatability and nutritional status. Independent of age and gender, these taste alterations have the potential to sway dietary choices, further complicating the management of CKD. The intricate interplay between CKD, inflammation, oxidative stress, and cardiovascular diseases is unraveled, emphasizing the profound repercussions on overall health. Additionally, the review extends its analysis to CKD’s broader impact on cognitive function, emotional well-being, taste perception, and endothelial dysfunction. Concluding with an emphasis on dietary interventions as crucial components in CKD management, this comprehensive review navigates the multifaceted dimensions of CKD, providing a nuanced understanding essential for developing targeted therapeutic strategies.
... Furthermore, there is a decrease in the clearance rate of norepinephrine, leading to abnormal neuroendocrine function within the cardiovascular system [32,33]. ...
Cardiac aging constitutes a significant risk factor for cardiovascular diseases prevalent among the elderly population. Urgent attention is required to prioritize preventive and management strategies for age-related cardiovascular conditions to safeguard the well-being of elderly individuals. In response to this critical challenge, the Aging Biomarker Consortium (ABC) of China has formulated an expert consensus on cardiac aging biomarkers. This consensus draws upon the latest scientific literature and clinical expertise to provide a comprehensive assessment of biomarkers associated with cardiac aging. Furthermore, it presents a standardized methodology for characterizing biomarkers across three dimensions: functional, structural, and humoral. The functional dimension encompasses a broad spectrum of markers that reflect diastolic and systolic functions, sinus node pacing, neuroendocrine secretion, coronary microcirculation, and cardiac metabolism. The structural domain emphasizes imaging markers relevant to concentric cardiac remodeling, coronary artery calcification, and epicardial fat deposition. The humoral aspect underscores various systemic (N) and heart-specific (X) markers, including endocrine hormones, cytokines, and other plasma metabolites. The ABC’s primary objective is to establish a robust foundation for assessing cardiac aging, thereby furnishing a dependable reference for clinical applications and future research endeavors. This aims to contribute significantly to the enhancement of cardiovascular health and overall well-being among elderly individuals.
... Blockage of the renin-angiotensin system (RAS) lowers BP and is recognized as a useful strategy for preventing incident and recurrent CVD events, including strokes and their sequelae such as vascular dementia (VaD) [17]. ARBs and ACEis are typical RAS-inhibiting antihypertensive medications that are widely used in clinical practice. ...
Purpose of Review
To provide an overview of the association between angiotensin II receptor blocker (ARB) use and cognitive outcomes.
Recent Findings
ARBs have previously shown greater neuroprotection compared to other anti-hypertensive classes. The benefits are primarily attributed to the ARB’s effect on modulating the renin-angiotensin system via inhibiting the Ang II/AT1R pathway and activating the Ang II/AT2R, Ang IV/AT4R, and Ang-(1–7)/MasR pathways. These interactions are associated with pleiotropic neurocognitive benefits, including reduced β-amyloid accumulation and abnormal hyperphosphorylation of tau, ameliorated brain hypo-fusion, reduced neuroinflammation and synaptic dysfunction, better neurotoxin clearing, and blood–brain barrier function restoration. While ACEis also inhibit AT1R, they simultaneously lower Ang II and block the Ang II/AT2R and Ang IV/AT4R pathways that counterbalance the potential benefits.
Summary
ARBs may be considered an adjunctive approach for neuroprotection. This preliminary evidence, coupled with their underlying mechanistic pathways, emphasizes the need for future long-term randomized trials to yield more definitive results.
... In the same vein, longitudinal studies that have analysed the effect of ACEIs or ARBs alone, in combination or in combination with CCBs or diuretics have been shown to be effective in reducing arterial stiffness, (Jatic et al., 2019), although the combination of ACEIs and ARBs is associated with more cardiovascular events than ACEIs alone. (Ma et al., 2010). ...
Aims: To synthesize and evaluate the available scientific evidence on the efficacy of antihypertensive drugs on arterial stiffness in patients with hypertension by using a network meta-analysis approach.
Methods: A systematic search of the MEDLINE (via PubMed), Scopus, and Web of Science databases was conducted to identify experimental studies addressing the effect of different antihypertensive drugs on arterial stiffness parameters (pulse wave velocity [PWV] and augmentation index [AIx]) in adults with hypertension. Comparative evaluation of the effect of antihypertensive drugs was performed by conducting a standard pairwise meta-analysis and a network meta-analysis for direct and indirect comparisons between antihypertensive drugs and placebo/other antihypertensive drugs. Analyses were performed including studies of any duration and only studies longer than 6 months length.
Results: Seventy-six studies were included in the main analysis and considering only studies longer than 6 months length, thiazide diuretics, ACEIs, ARBs, the ACEI/ARB combination, the ACEI/CCB combination, and the ARB/CCB combination showed a higher effect on reducing PWV, and ACEIs and ARBs on reducing AIx.
Conclusion: Our research provides evidence that antihypertensive medications are an effective way to treat arterial stiffness in adults with hypertension. Based on our findings, patients with hypertension who have greater levels of arterial stiffness may benefit from using thiazide diuretics, ACEIs, ARBs, the ACEI/ARB combination, the ACEI/CCB combination, and the ARB/CCB combination.
Systematic Review Registration: PROSPERO (CRD42021276360).
... Ativação da cascata da RAAS, na hipertensão, está associada com remodelamento cardíaco do ventrículo esquerdo 52 . Inicialmente, esta hipertrofia do ventrículo esquerdo (HVE) serve como uma resposta adaptativa ou compensatória para alguns estímulos patológicos, tais como infarto do miocárdio 53 , hipertensão 54 , e outras causas como o estresse oxidativo cardiovascular, por exemplo, e lesão de isquemia-reperfusão 55 . ...
... Blockage of renin-angiotensin-aldosterone system (RAAS) by either angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin-receptor blockers (ARBs) is considered the first-choice of drugs for treatment of hypertension, heart failure and chronic kidney diseases [1]. In RAAS system, there are two pathways. ...
Background
Renin–angiotensin–aldosterone system (RAAS) is hypothesized to be in the center of COVID pathophysiology as the angiotensin converting enzyme 2 (ACE2) represents the main entrance of the virus, thus there is a need to address the effect of chronic use of RAAS blockers, as in case of treatment of cardiovascular diseases, on the expression of ACE2. Accordingly, this study aimed to clarify the effect of ACE inhibitors (ACEIs) and angiotensin-receptor blockers (ARBs) on ACE2 and to assess the correlation between ACE2 and several anthropometric and clinic-pathological factors.
Methods
A total of 40 healthy controls and 60 Egyptian patients suffering from chronic cardiovascular diseases were enrolled in this study. Patients were divided into 40 patients treated with ACEIs and 20 patients treated with ARBs. Serum ACE2 levels were assessed by ELISA.
Results
Assessment of serum ACE2 level in different groups showed a significant difference between ACEIs and healthy groups and ACEIs and ARBs group, while there was no difference between ARBs and healthy. Multivariate analysis using ACE2 level as constant and age, female sex, ACEIs use and myocardial infarction (MI) showed that there was a significant effect of female sex and ACEIs use on ACE2 level with no effect of age, MI and diabetes.
Conclusion
ACE2 levels varied between ACEIs and ARBs. It tends to be lower in ACEIs group and there is a strong positive association between ACE2 level and the female sex. This needs to be considered in Future studies to further understand the relationship between gender, sex hormones and ACE2 level.
Trial registration
Retrospectively registered ClinicalTrials.gov ID: NCT05418361 (June 2022).
Graphical abstract
... Interestingly, βAR stimulation in the brain triggers Antidiuretic hormone (ADH) or vasopressin that stimulates the adrenal cortex of the kidney to release more Aldosterone and thus leads to tubular salt-ion (Na+, Cl−) reabsorption, K+ excretion, and water retention [70]. So, low perfusion pressure in the juxtaglomerular apparatus is responsible for renin secretion from the kidney that converts angiotensin (Ang) to Angiotensin II (Ang II), and this vicious cycle of Renin-Angiotensin-Aldosterone system cause vasoconstriction and increases arterial pressure [45,134,180]. However, it has been noticed that high intracellular glucose levels and leptin levels promote the activation of the hexosamine biosynthetic pathway leading to the O-Glc-NAcylation (involved in cardiac contractile function via calcium homeostasis) and directly stimulating the production of Ang II leading to the activation of RAS in cardiomyocytes and cell death [180,243]. ...
Non-communicable lifestyle diseases and related mortality are increasing rapidly over the last few decades. Obesity is one of the major concerning problems leading to obesity-related metabolic syndrome like cardiovascular diseases, type 2 diabetes mellitus, polycystic ovarian syndrome etc. About 40–75% of obesity cases arise through genetic inheritance. The genetic and epigenetic alterations involved in the disease manifestation are controlled by the environmental factors including both physical and physiological factors. In both the prenatal and postnatal stages of the concerned individual, the epigenetic modifications are controlled by the environmental factors subsequently leading to genomic alterations and predisposition of a disease. In this review, we have assimilated the studies from last 20 years discussing the genetic and epigenetic mechanisms of the predominant non-communicable diseases and the environmental factors affecting them. This review also focuses on the inter-relationship of the concerned environmental factors and their variations in a disease specific pattern. The environmental factors including diet, physical inactivity, stress, education, pollutants, addictions etc. have been found to portray significant role in the disease outcomes. The family income, exposure to heavy metal pollutants, noise pollution, endocrine disruptors and external stress inducing agents can’t be controlled by the subject. Instead, controlling the diet pattern, family health, sleeping duration, screen time, addiction of alcohol or smoking and physical activity can provide significant benefit henceforth lowering the risk of obesity, CVD, T2DM and PCOD.
... The renin-angiotensin system is an important regulatory system for maintaining cardiovascular and renal function. Therefore, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers have emerged as first-line treatments for conditions such as hypertension and heart failure [4]. Here in this study, we focus on targeting type-1 angiotensin II receptor (AGTR1) among the several potential druggable targets. ...
Cardiovascular diseases (CVDs) are the leading cause of death and morbidity globally. The renin-angiotensin system is an important regulatory system for maintaining cardiovascular and renal function. Therefore, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers have emerged as first-line treatments for conditions such as hypertension and heart failure. Currently available synthetic medications used to treat various CVDs have been linked with various adverse effects. Therefore, this study focuses on targeting type-1 angiotensin II receptor (AGTR1) by natural compounds. The ZINC database natural compounds and standard ISSN 0973-2063 (online) 0973-8894 (print) ©Biomedical Informatics (2023) Bioinformation 19(3): 284-289 (2023) 285 AGTR1 inhibitors have been screened against the AGTR1 active site. The results showed that five compounds, namely ZINC85625504, ZINC62001623, ZINC70666587, ZINC06624086, and ZINC95486187, had similar binding energies to established AGTR1 inhibitors. These compounds were found to interact with crucial AGTR1 residues, indicating their potential as AGTR1 inhibitors. Moreover, the hit compounds demonstrated favorable drug-like characteristics and warrant further investigation for their potential use in managing CVD.
... The renin-angiotensin system is an important regulatory system for maintaining cardiovascular and renal function. Therefore, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers have emerged as first-line treatments for conditions such as hypertension and heart failure [4]. Here in this study, we focus on targeting type-1 angiotensin II receptor (AGTR1) among the several potential druggable targets. ...
Cardiovascular diseases (CVDs) are the leading cause of death and morbidity globally. The renin-angiotensin system is an important regulatory system for maintaining cardiovascular and renal function. Therefore, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers have emerged as first-line treatments for conditions such as hypertension and heart failure. Currently available synthetic medications used to treat various CVDs have been linked with various adverse effects. Therefore, this study focuses on targeting type-1 angiotensin II receptor (AGTR1) by natural compounds. The ZINC database natural compounds and standard AGTR1 inhibitors have been screened against the AGTR1 active site. The results showed that five compounds, namely ZINC85625504, ZINC62001623, ZINC70666587, ZINC06624086, and ZINC95486187, had similar binding energies to established AGTR1 inhibitors. These compounds were found to interact with crucial AGTR1 residues, indicating their potential as AGTR1 inhibitors. Moreover, the hit compounds demonstrated favorable drug-like characteristics and warrant further investigation for their potential use in managing CVD.
... An ideal drug candidate should selectively target the RBD without interacting with ACE2 to avoid possible side effects linked to angiotensin physiology [90]. Docking studies with the complex RBD-ACE2 are employed in order to examine whether OEU and OC are able to disrupt the interaction of RBD with ACE2 host receptor protein. ...
Since there is an urgent need for novel treatments to combat the current coronavirus disease 2019 (COVID-19) pandemic, in silico molecular docking studies were implemented as an attempt to explore the ability of selected bioactive constituents of extra virgin olive oil (EVOO) to act as potent SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) antiviral compounds, aiming to explore their ability to interact with SARS-CoV-2 Spike key therapeutic target protein. Our results suggest that EVOO constituents display substantial capacity for binding and interfering with Spike (S) protein, both wild-type and mutant, via the receptor-binding domain (RBD) of Spike, or other binding targets such as angiotensin-converting enzyme 2 (ACE2) or the RBD-ACE2 protein complex, inhibiting the interaction of the virus with host cells. This in silico study provides useful insights for the understanding of the mechanism of action of the studied compounds at a molecular level. From the present study, it could be suggested that the studied active phytochemicals could potentially inhibit the Spike protein, contributing thus to the understanding of the role that they can play in future drug designing and the development of anti-COVID-19 therapeutics.
... The clinical use of inhibitors of the renin-angiotensin-aldosterone system has been linked to the reversal of some of the alterations of ECM, particularly the decrease in the total contents of collagen and its cross-linked fraction, translating into decreased fibrosis, stiffness and a lower left ventricular mass [38]. This has been demonstrated particularly with reference to angiotensin-converting enzyme inhibitors (ACEI) in the prevention and treatment of ischemic and non-ischemic HF [39] and MRAs [34,40], and was even more pronounced in patients receiving angiotensin receptor neprilysin inhibitors (ARNI) [41][42][43]. ...
The progress of contemporary cardiovascular therapy has led to improved survival in patients with myocardial disease. However, the development of heart failure (HF) represents a common clinical challenge, regardless of the underlying myocardial pathology, due to the severely impaired quality of life and increased mortality comparable with malignant neoplasms. Left ventricular ejection fraction (LVEF) is the main index of systolic function and a key predictor of mortality among HF patients, hence its improvement represents the main indicator of response to instituted therapy. The introduction of complex pharmacotherapy for HF, increased availability of cardiac-implantable electronic devices and advances in the management of secondary causes of HF, including arrhythmia-induced cardiomyopathy, have led to significant increase in the proportion of patients with prominent improvement or even normalization of LVEF, paving the way for the identification of a new subgroup of HF with an improved ejection fraction (HFimpEF). Accumulating data has indicated that these patients share far better long-term prognoses than patients with stable or worsening LVEF. Due to diverse HF aetiology, the prevalence of HFimpEF ranges from roughly 10 to 40%, while the search for reliable predictors and genetic associations corresponding with this clinical presentation is under way. As contemporary guidelines focus mainly on the management of HF patients with clearly defined LVEF, the present review aimed to characterize the definition, epidemiology, predictors, clinical significance and principles of therapy of patients with HFimpEF.
... This product is an effective vasopressor and releases aldosterone. ACE also inactivates bradykinin, which is a potent vasodilator 14 . Genetic ACE metabolism has been associated with microvascular complications of diabetes, progression of Alzheimer's disease, severe acute respiratory syndrome, renal tubular dysgenesis, and susceptibility to myocardial infarction 15 . ...
Background: Angiotensin I is converted to angiotensin II by an angiotensin-converting enzyme, which is an important component of renin-angiotensin framework. Multifactorial chronic kidney disease includes risk factors such as hypertension, obesity, inherited factors, and diabetes. A genetic factor associated with premature signs of renal failure is predominantly increased arterial hypertension and albumin excretion, which add to the pathophysiological movement of disintegration in renal capacity. This enzymatic assay aimed to detect ACE levels in various renal patients compared with controls to confirm the relationship between ACE quality polymorphism and enzymatic ACE levels. Materials and Methods: The study population of our study included 56 patients with chronic kidney disease. Who was confirmed to have chronic kidney disease after being diagnosed in the dialysis ward of the tertiary care hospital. Results: A total of 56 chronic kidney disease were enrolled. Mean age of patients were 55.1±13.6. Among total recruited patients, 60% male patients and 40% were female patients. The HDL, and LDL were lower in chronic kidney disease patients than control group. While BMI, total cholestrol, triglyceride, systolic blood pressure, diastolic blood pressure, and ACE level were found higher in CKD patients than control group. The frequency of genotypes ACE II, ID, and DD in patients groups was 12 (12.43%), 28 (48.21%), and 17 (30.35%). Conclusion: Our study result indicates that the D allele is involved in the progression of chronic diseases. When we look at the frequency of I and D alleles it clearly shows that the frequency of the D allele is significantly higher in patients with CKD than the frequency of the I allele. Keywords: ACE, CKD, Renal patients, Polymorphism
... This leads to develop hypertension which is a risk factor of cardiovascular diseases. Angiotensin converting enzyme (ACE) catalyzes the formation of angiotensin II (a physiologically potent vasoconstrictor) by cleavage of angiotensin 1 and so inhibition of ACE has been considered as one of the appropriate therapeutic approaches for regulating the blood pressure [29]. In this investigation, MEAL also showed potent inhibition against ACE (IC50: 9.26 ± 0.71 µg/mL) as compared with captopril, a standard ACE inhibitor (IC50 of 6.38 ± 0.42 µg/mL) (Table 1). ...
... This leads to develop hypertension which is a risk factor of cardiovascular diseases. Angiotensin converting enzyme (ACE) catalyzes the formation of angiotensin II (a physiologically potent vasoconstrictor) by cleavage of angiotensin I and so inhibition of ACE has been considered as one of the appropriate therapeutic approaches for regulating the blood pressure 35 . In this investigation, MBLE inhibited ACE (IC50:13.34±1.05 ...
... Important molecular targets in heart failure with decreased ejection fraction include ACEIs, ARBs, and mineralocorticoid antagonists because of their neurohormonal regulation of the renin-angiotensinaldosterone system (15) . Reduced catecholamine stimulation and myocardial oxygen demand by beta blockers reduces the rate of adverse remodeling from cardiac myocyte hypertrophy as well as supply-demand difference (16) . ...
... Ever since captopril became available in the 1980s [3], this drug class has been commonly used to treat cardiovascular disease, including hypertension, coronary artery disease, and heart failure, as well as other comorbid conditions, such as diabetic nephropathy [4][5][6][7]. ACE inhibitors act by inhibiting the activity of ACE, a key component of the renin-angiotensin-aldosterone system, thereby preventing the conversion of angiotensin I to angiotensin II [8,9]. Angiotensin II suppression leads to several physiologic consequences, such as relaxation of arteriolar vascular smooth muscle, decreased aldosterone secretion, and neurohormonal modulation, resulting in clinical benefits in a variety of cardiovascular diseases [10]. ...
Background:
Although angiotensin-converting enzyme (ACE) inhibitors are among the most-prescribed medications in the world, the extent to which they increase the risk of adverse effects remains uncertain. This study aimed to systematically determine the adverse effects of ACE inhibitors versus placebo across a wide range of therapeutic settings.
Methods:
Systematic searches were conducted on PubMed, Web of Science, and Cochrane Library databases. Randomized controlled trials (RCTs) comparing an ACE inhibitor to a placebo were retrieved. The relative risk (RR) and its 95% confidence interval (95% CI) were utilized as a summary effect measure. A random-effects model was used to calculate pooled-effect estimates.
Results:
A total of 378 RCTs fulfilled the eligibility criteria, with 257 RCTs included in the meta-analysis. Compared with a placebo, ACE inhibitors were associated with an significantly increased risk of dry cough (RR = 2.66, 95% CI = 2.20 to 3.20, p < 0.001), hypotension (RR = 1.98, 95% CI = 1.66 to 2.35, p < 0.001), dizziness (RR = 1.46, 95% CI = 1.26 to 1.70, p < 0.001), and hyperkalemia (RR = 1.24, 95% CI = 1.01 to 1.52, p = 0.037). The risk difference was quantified to be 0.037, 0.030, 0.017, and 0.009, respectively.
Conclusions:
We quantified the relative risk of numerous adverse events associated with the use of ACE inhibitors in a variety of demographics. This information can help healthcare providers be fully informed about any potential adverse consequences and make appropriate suggestions for their patients requiring ACE inhibitor therapy.
... The most classical view of AT1R emphasizes its role as an endocrine regulator of renal sodium balance and blood pressure. But recent evidence pointed out its other pathological effects including inflammation and fibrosis (Ma et al., 2010). It is reported that AT1R promotes the phosphorylation of NF-κB at the p65 subunit, a key step in activating NF-κB, leading to the gene expression of chemokines interleukin-6 and inflammatory adhesion molecules in diabetes (Chao et al., 2017). ...
Renal tubulointerstitial fibrosis (TIF), characterized by epithelial-to-mesenchymal transition (EMT) of renal tubular epithelial cells, is the typical pathological alteration in diabetic nephropathy. Gentiopicroside (GPS), a natural compound with anti-inflammatory activity, has been demonstrated to alleviate glomerulosclerosis, whereas whether GPS inhibits TIF via regulating inflammation remains unclear. In this study, diabetic db/db mice and high glucose (HG)-stimulated renal tubular epithelial cells (NRK-52E) were applied to explore the effects and mechanisms of GPS on TIF. The results in vivo showed that GPS effectively improves glycolipid metabolism disorder, renal dysfunction, and TIF. In particular, GPS treatment reversed the abnormal expressions of EMT marker proteins including elevated α-smooth muscle actin and vimentin and decreased E-cadherin in the kidney of db/db mice. Moreover, GPS treatment also inhibited protein expressions of angiotensinⅡ type 1 receptor (AT1R) and CK2α and the activation of the NF-κB pathway. Importantly, the aforementioned effects of GPS acted in vivo were further observed in vitro in HG-stimulated NRK-52E cells, which were independent of its effects on glucose and lipid-lowering activity but were reversed by AT1R over-expression. Together, our results indicate that GPS that directly inhibits the CK2/NF-κB inflammatory signaling pathway via AT1R may also contribute to the amelioration of TIF in diabetes.
This study aimed to investigate the role of circSlc8a1 in cardiac hypertrophy (CH), a pathological change in various cardiovascular diseases.
An in vitro CH model was established using angiotensin II (AngII) treated H9c2 cells, followed by western blotting and RT-qPCR for detecting relative expressions. Cell viability and proliferation were analyzed using CCK-8 and EdU assays, while lactate dehydrogenase (LDH), reactive oxygen species (ROS), glutathione (GSH), and iron levels were determined using corresponding kits. Moreover, dual-luciferase reporter and RNA pull-down assays were performed to demonstrate whether miR-673-5p is bound to circSlc8a1 or transferrin receptor (TFRC).
The results indicated that the expressions of circSlc8a1 and TFRC were increased, while miR-673-5p was decreased in the AngII treated H9c2 cells. The ferroptosis inhibitor treatment decreased the atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and β-major histocompatibility complex (β-MHC) protein expressions, and circSlc8a1 expressions. Knocking down of circSlc8a1 inhibited promoted the cell viability and proliferation, increased the GSH content, glutathione peroxidase 4, and solute carrier family 7 member 11 protein expressions, and decreased the LDH, ROS, iron levels, and RAS protein expressions. The MiR-673-5p inhibitor antagonized the role of si-circSlc8a1, and the over-expressed TFRC reversed the miR-673-5p mimicking effects in AngII treated H9c2 cells.
CircSlc8a1 promoted the ferroptosis in CH via regulating the miR-673-5p/TFRC axis.
This review provides an overview of the key role played by perivascular adipose tissue (PVAT) in the protection of cardiovascular health. PVAT is a specific type of adipose tissue that wraps around blood vessels and has recently emerged as a critical factor for maintenance of vascular health. Through a profound exploration of existing research, this review sheds light on the intricate structural composition and cellular origins of PVAT, with a particular emphasis on combining its regulatory functions for vascular tone, inflammation, oxidative stress, and endothelial function. The review then delves into the intricate mechanisms by which PVAT exerts its protective effects, including the secretion of diverse adipokines and manipulation of the renin-angiotensin complex. The review further examines the alterations in PVAT function and phenotype observed in several cardiovascular diseases, including atherosclerosis, hypertension, and heart failure. Recognizing the complex interactions of PVAT with the cardiovascular system is critical for pursuing breakthrough therapeutic strategies that can target cardiovascular disease. Therefore, this review aims to augment present understanding of the protective role of PVAT in cardiovascular health, with a special emphasis on elucidating potential mechanisms and paving the way for future research directions in this evolving field.
Functional foods are rich in nutrients; they affect the physical and physiological parameters of an organism. Functional foods sometimes called as nutraceuticals rich foods like probiotics, prebiotics, functional drinks, beverages, spreads, bakery products and functional cereals etc. Functional foods are very from places to places and continent to continent.Its perspective is different in Asian continents, American continent and European continents. Phytoconstituents like phenolics, flavonoids, alkaloids and carotenoids are mainly present in functional foods and it can be taken for treatment of some dreadful disease like cardio vascular disease, diabetes, neurological disorders and cancer etc. Clinical trial also carried out on functional foods and few products also came in to market. This chapter briefly considered all aspects of functional foods and its role in controlling the patho- physiology of humans.
There has been a significant shift in the perception of hypertension as an important contributor to the global disease burden. Approximately 6% and 8% of pregnancies are affected by hypertension, which can adversely affect the mother and the fetus. Furthermore, a hypertensive individual is at increased risk of developing kidney disease, arterial hardening, eye damage, and strokes. Using angiotensin receptor blockers (ARBs) is widespread in treating hypertension, heart failure, coronary artery disease, and diabetic nephropathy. Despite this, some ARBs have limited use due to their poor oral bioavailability and water solubility. To tackle this, a variety of nanoparticle (NP)‐based systems, such as polymeric NPs (i.e., dendrimers), polymeric micelles, polymer‐drug conjugates, lipid NPs, nanoemulsions, self‐emulsifying drug delivery systems (SEDDS), solid lipid NPs (SLNs), nanostructured lipid carriers (NLCs), carbon‐based nanocarriers, inorganic NPs, and nanocrystals, have been recently developed for efficient delivery of losartan, Valsartan (Val), Olmesartan (OLM), Telmisartan (TEL), Candesartan, Eprosartan, Irbesartan, and Azilsartan to target cells. This review article provides a literature‐based comparison of the various classes of ARBs, their mechanisms of action, and an overview of the nanoformulations developed for ARB delivery and successfully applied to managing hypertension, diabetic complications, and other conditions.
The pursuit of knowledge is an intrinsic characteristic of the human species. Throughout history, we have endeavored to unravel the mysteries of the universe, to understand the intricate workings of our world, and to harness the forces of nature for the betterment of our lives. Science and technology have been the driving forces behind our progress, leading us to astonishing discoveries and revolutionary inventions.
In this rapidly evolving era, where boundaries are constantly being pushed and new frontiers are being explored, it is imperative that we stay abreast of the latest advancements in science and technology. This book, "Advances in Science and Technology," serves as a comprehensive compilation of cutting-edge research and breakthrough innovations that are shaping our present and defining our future.
Oral oncolytic treatment options have expanded over the last decade and have brought to light the need to monitor and manage cardiovascular (CV) disease in patients being treated with these therapies. There is a need to assess CV risk before patients receive oral oncolytic therapy with known potential to cause negative CV sequelae such as left ventricular dysfunction, hypercholesterolemia, hypertension, and arrhythmias. The review highlights the need to evaluate traditional CV risk factors and their association with the development and progression of cancer. Additionally, this review suggests approaches to monitor for CV adverse events and manage CV disease during and after treatment with oral oncolytic therapy. Key guideline recommendations are reviewed and highlight specific approaches to minimize CV harm for patients exposed to oral oncolytic therapy. Careful monitoring and patient-centered decision making is key in choosing appropriate therapies. A multidisciplinary approach between oncologists, cardio-oncologists, pharmacists, and other members of the healthcare team is essential in navigating cardiac toxicities.
Background
The best medical therapy to control hypertension following abdominal aortic aneurysm repair is yet to be determined. We therefore examined whether treatment with renin‐angiotensin‐aldosterone system inhibitors (RAASIs) versus beta blockers influenced postoperative and 1‐year clinical end points following abdominal aortic aneurysm repair in a Medicare‐linked database.
Methods and Results
All patients with hypertension undergoing endovascular aneurysm repair and open aneurysm repair in the Vascular Quality Initiative Vascular Implant Surveillance and Interventional Outcomes Network database between 2003 and 2018 were included. Patients were divided into 2 groups based on their preoperative and discharge medications, either RAASIs or beta blockers. Our cohort included 8789 patients, of whom 3523 (40.1%) were on RAASIs, and 5266 (59.9%) were on beta blockers. After propensity score matching, there were 3053 matched pairs of patients in each group. After matching, RAASI use was associated with lower risk of postoperative mortality (odds ratio [OR], 0.3 [95% CI, 0.1–0.6]), myocardial infarction (OR, 0.1 [95% CI, 0.03–0.6]), and nonhome discharge (OR, 0.6 [95% CI, 0.5–0.7]). Before propensity score matching, RAASI use was associated with lower 1‐year mortality (hazard ratio [HR], 0.4 [95% CI, 0.4–0.5]) and lower risk of aneurysmal rupture (HR, 0.7 [95% CI, 0.5–0.9]). These results persisted after propensity score matching for mortality (HR, 0.4 [95% CI, 0.4–0.5]) and aneurysmal rupture (HR, 0.7 [95% CI, 0.5–0.9]).
Conclusions
In this large contemporary retrospective cohort study, RAASI use was associated with favorable postoperative outcomes compared with beta blockers. It was also associated with lower mortality and aneurysmal rupture at 1 year of follow‐up.
The potential of targeting the Renin-Angiotensin-Aldosterone System (RAAS) as a treatment for the coronavirus disease 2019 (COVID-19) is currently under investigation. One way to combat this disease involves the repurposing of angiotensin receptor blockers (ARBs), which are antihypertensive drugs, because they bind to angiotensin-converting enzyme 2 (ACE2), which in turn interacts with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein. However, there has been no in silico analysis of the potential toxicity risks associated with the use of these drugs for the treatment of COVID-19. To address this, a network-based bioinformatics methodology was used to investigate the potential side effects of known Food and Drug Administration (FDA)-approved antihypertensive drugs, Sartans. This involved identifying the human proteins targeted by these drugs, their first neighbors, and any drugs that bind to them using publicly available experimentally supported data, and subsequently constructing proteomes and protein–drug interactomes. This methodology was also applied to Pfizer’s Paxlovid, an antiviral drug approved by the FDA for emergency use in mild-to-moderate COVID-19 treatment. The study compares the results for both drug categories and examines the potential for off-target effects, undesirable involvement in various biological processes and diseases, possible drug interactions, and the potential reduction in drug efficiency resulting from proteoform identification.
Dihydroartemisinin is currently now being studied for the treatment of diseases. The mechanism of action of dihydroartemisinin on cardiovascular diseases is unclear. We explored the effect of dihydroartemisinin on the activity of cardiac fibroblasts and the underlying mechanism. The cardiac fibroblasts were divided into blank control group, dihydroartemisinin group, vascular angiotensin II (AngII) group and angiotensin II+dihydroartemisinin group followed by analysis of cell proliferation, Col I and FN levels, and the levels of TGF- β 1, α -SMA and IGF-I. The morphology of myocardial fibroblasts was spindle-shaped. Further immunofluorescence staining assessed positive expression of Vimentin of the myocardial fibroblasts and no expression of α -SMA, which confirmed the successful culture of the myocardial fibroblasts. Overexpression of AngII significantly promoted the proliferation ability of mouse cardiac fibroblasts, which was significantly reduced after dihydroartemisinin treatment. As shown by RT-qPCR, TGF- β 1, α -SMA and IGF-I levels in AngII mice increased, while their levels reduced after dihydroartemisinin intervention. After overexpression of AngII in cardiomyocytes, cell proliferation and colonies formation increased and decreased after dihydroartemisinin treatment, suggesting that dihydroartemisinin inhibited the growth of cardiomyocytes. It showed that dihydroartemisinin could alleviate the expression of AngII-induced activation markers of mouse cardiac fibroblasts. Therefore, our research confirms that dihydroartemisinin plays an important role in anti-myocardial fibrosis, mainly through regulating the expression of TGF- β 1.
The potential of targeting the Renin-Angiotensin-Aldosterone System (RAAS) as a treatment for the coronavirus disease 2019 (COVID-19) is currently under investigation. One way to combat this disease involves the repurposing of angiotensin receptor blockers (ARBs), which are antihypertensive drugs, because they bind to angiotensin-converting enzyme 2 (ACE2), which in turn interacts with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein. However, there has been no in silico analysis of the potential toxicity risks associated with the use of these drugs for the treatment of COVID-19. To address this, a network-based bioinformatics methodology was used to investigate the potential side effects of known Food and Drug Administration (FDA)-approved antihypertensive drugs, Sartans. This involved identifying the human proteins targeted by these drugs, their first neighbors, and any drugs that bind to them using publicly available experimentally supported data, and subsequently constructing proteomes and protein–drug interactomes. This methodology was also applied to Pfizer’s Paxlovid, an antiviral drug approved by the FDA for emergency use in mild-to-moderate COVID-19 treatment. The study compares the results for both drug categories and examines the potential for off-target effects, undesirable involvement in various biological processes and diseases, possible drug interactions, and the potential reduction in drug efficiency resulting from proteoform identification.
Objective:
To compare the clinical outcomes of patients with acute myocardial infarction with renal impairment (AMI-RI) treated with either angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) in real-world clinical settings.
Patients and methods:
A total of 4790 consecutive patients with AMI-RI between November 1, 2011, and December 31, 2015, were subdivided into ACEI (n=2845) and ARB (n=1945) treatment groups. The primary end points were major adverse cardiac and cerebrovascular events, including all-cause mortality, nonfatal myocardial infarction, any revascularization, cerebrovascular accident, rehospitalization, and stent thrombosis. Propensity score matching (PSM) was used to adjust for group differences.
Results:
The ARB group had a significantly higher incidence of major adverse cardiac and cerebrovascular events (at 3-year follow-up) than the ACEI group according to the unadjusted analysis (3-year hazard ratio [HR], 1.60; 95% CI, 1.43 to 1.78) and the PSM-adjusted analysis (3-year HR, 1.34; 95% CI, 1.15 to 1.56). However, any revascularization (3-year HR, 1.21; 95% CI, 0.95 to 1.54) and rehospitalization (3-year HR, 1.21; 95% CI, 0.88 to 1.67) were not significantly different between groups in the PSM-adjusted analysis. Compared with the ARB group, the ACEI group had lower rates of all-cause mortality at estimated glomerular filtration rates of at least 15 or less than 90 mL/min/1.73 m2 in the unadjusted data and at least 60 or less than 90 mL/min/1.73 m2 in the PSM-adjusted analysis.
Conclusion:
Treatment with ACEIs seemed to be more beneficial than treatment with ARBs for patients with AMI-RI; further prospective studies are required to confirm these results.
Objective . The purpose of this review is to highlight the pathophysiological mechanisms of the sequential formation of left ventricular hypertrophy (LVH), left ventricular dysfunction and chronic heart failure (CHF) in patients with hypertension (HTN), diagnostic and therapeutical issues of CHF with both reduced and preserved ejection fraction (EF). HTN is the main risk factor for cardiovascular diseases and is accompanied by damage of target organs, among which LVH is of particular importance. On the one hand, development of LVH is the consequence of increased load on the heart muscle and neurohumoral stimuli, and on the other hand, it is an independent risk factor for myocardial infarction, stroke, cardiac arrhythmias and CHF. HTN precedes newly developed heart failure in 91 % of patients with a predominance of CHF with a preserved EF according to the Framingham Heart Study. To date, different drugs can improve the prognosis of patients with HTN, CHF with reduced EF and to induce LVH regression. However, the issues of effective treatment of patients with CHF with preserved EF are still insufficiently studied.
Normal circulatory function is a key determinant of disease-free life expectancy (healthspan). Indeed, pathologies affecting the cardiovascular system, which are growing in prevalence, are the leading cause of global morbidity, disability and mortality, whereas the maintenance of cardiovascular health is necessary to promote both organismal healthspan and lifespan. Therefore, cardiovascular ageing might precede or even underlie body-wide, age-related health deterioration. In this Review, we posit that eight molecular hallmarks are common denominators in cardiovascular ageing, namely disabled macroautophagy, loss of proteostasis, genomic instability (in particular, clonal haematopoiesis of indeterminate potential), epigenetic alterations, mitochondrial dysfunction, cell senescence, dysregulated neurohormonal signalling and inflammation. We also propose a hierarchical order that distinguishes primary (upstream) from antagonistic and integrative (downstream) hallmarks of cardiovascular ageing. Finally, we discuss how targeting each of the eight hallmarks might be therapeutically exploited to attenuate residual cardiovascular risk in older individuals.
Background:
Angiotensinogen is the proximal precursor of the angiotensin peptide hormones of the renin-angiotensin-aldosterone system (RAAS). Clinical trials are ongoing targeting angiotensinogen for the treatment of hypertension and heart failure. The epidemiology of angiotensinogen is not well defined, particularly its relationship to ethnicity, sex, and blood pressure (BP)/hypertension.
Objectives:
The authors sought to determine the relationship of circulating angiotensinogen levels to ethnicity, sex, BP, incident hypertension, and prevalent hypertension in a modern sex-balanced ethnically diverse cohort.
Methods:
Plasma angiotensinogen levels were measured in 5,786 participants from the MESA (Multi-Ethnic Study of Atherosclerosis). Linear, logistic, and Cox proportional hazards models were utilized to examine the associations of angiotensinogen with BP, prevalent hypertension, and incident hypertension, respectively.
Results:
Angiotensinogen levels were significantly higher in females than males and differed across self-reported ethnicities with the ordering (from highest to lowest): White, Black, Hispanic, and Chinese adults. Higher levels were associated with higher BP and odds of prevalent hypertension, after adjusting for other risk factors. Equivalent relative differences in angiotensinogen were associated with greater differences in BP in males vs females. In males not taking RAAS-blocking medications, a standard deviation increment in log-angiotensinogen was associated with 2.61 mm Hg higher systolic BP (95% CI: 1.49-3.80), while in females the same increment in angiotensinogen was associated with 0.97 mm Hg higher systolic BP (95% CI: 0.30-1.65).
Conclusions:
Significant differences in angiotensinogen levels are present between sexes and ethnicities. A positive association is present between levels and prevalent hypertension and BP, which differs between sexes.
Upon myocardial infarction (MI), activated cardiac fibroblasts (CFs) begin to remodel the myocardium, leading to cardiac fibrosis and even heart failure. No therapeutic approaches are currently available to prevent the development of MI-induced pathological fibrosis. Most pharmacological trials fail from poor local drug activity and side effects caused by systemic toxicity, largely due to the lack of a heart-targeted drug delivery system that is selective for activated CFs. Here, we developed a reduced glutathione (GSH)-responsive nanoparticle platform capable of targeted delivering of drugs to activated CFs within the infarct area of a post-MI heart. Compared with systemic drug administration, CF-targeted delivery of PF543, a sphingosine kinase 1 inhibitor identified in a high-throughput antifibrotic drug screening, had higher therapeutic efficacy and lower systemic toxicity in a MI mouse model. Our results provide a CF-targeted strategy to deliver therapeutic agents for pharmacological intervention of cardiac fibrosis.
The Renin-Angiotensin-Aldosterone System (RAAS), which regulates plasma sodium levels, arterial blood pressure, and extracellular volume, is a crucial component of the human body. Angiotensin II is a multifunctional effector peptide hormone that is created when the renin enzyme, which is produced by the kidneys, interacts with angiotensinogen. RAAS activation and the ensuing hypertension, cell proliferation, inflammation, and fibrosis affect every organ. Numerous acute and chronic illnesses can be brought on by an imbalance between renin and angiotensin II. The advancement of kidney disease is correlated with proteinuria and a decline in renal function. RAAS over-activity promotes the emergence of a variety of clinical diseases, including the development of chronic kidney disease (CKD). In order to reduce blood pressure and proteinuria in patients with chronic kidney disease (CKD), reno preventive treatment has long depended on inhibiting the renin-angiotensin-aldosterone system (RAAS). According to research, RAAS inhibitors play a preventive effect in both the early and late stages of kidney disease by preventing proteinuria, kidney fibrosis, and slow decline in renal function. An overview of the RAAS pathway, its function in the kidney, and RAAS pathway blocking techniques for enhancing long-term outcomes in CKD patients are covered in this chapter.KeywordsReninAldosteroneAngiotensinogenKidneyRenin inhibitorsChronic kidney disease
The Renin angiotensin system (RAS) plays an essential role in regulating the angiotensin II levels in the body and maintaining cardiovascular homeostasis. However, overactivation of RAS leads to hypertension and cardiac overload, especially in the left ventricle, causing cardiac hypertrophy. As a compensatory mechanism, the heart muscles undergo myocardial hypertrophy to maintain the cardiovascular function. Progression of cardiac hypertrophy along with other factors leads to heart failure. RAS mediated high blood pressure is one of the major risk factors that initiates pathological changes in the coronary blood vessels, sometimes resulting in heart attack and stroke. The results of preclinical and limited number of clinical studies demonstrated that quercetin possesses cardioprotective effects to prevent hypertension, cardiac hypertrophy, and heart failure. The multiple benefits of quercetin are attributed to ACE inhibition, strong antioxidant and anti-inflammation properties and protection of endothelial function which collectively prevent coronary heart disease, hypertension, myocardial hypertrophy and heart failure. This review aims to provide an overview of the current knowledge about the impact of RAS in causing CVDs, to highlight cellular and molecular mechanisms of quercetin involved in ACE inhibition via RAS pathway and to slow down the progression of cardiac hypertrophy and heart failure. Despite having an enormous therapeutic potential, the usefulness of quercetin at present is limited due to its low aqueous solubility and oral bioavailability. Different formulations are being developed to enhance the bioavailability of quercetin by employing novel drug delivery systems which will pave the ways for discovering cost-effective, affordable, and safe drugs for treating CVDs.KeywordsRenin angiotensin systemCardiac hypertrophyHeart failureCardiovascular diseasesQuercetinFlavonoidsQuercetin formulations
Coronavirus disease 2019 is caused by SARS-CoV-2 and is more severe in the elderly, racial minorities, and those with comorbidities such as hypertension and diabetes. These pathologies are often controlled with medications involving the renin–angiotensin–aldosterone system (RAAS). RAAS is an endocrine system involved in maintaining blood pressure and blood volume through components of the system. SARS-CoV-2 enters the cells through ACE2, a membrane-bound protein related to RAAS. Therefore, the use of RAAS inhibitors could worsen the severity of COVID-19’s symptoms, especially amongst those with pre-existing comorbidities. Although a vaccine is currently available to prevent and reduce the symptom severity of COVID-19, other options, such as nitric oxide and hydrogen sulfide, may also have utility to prevent and treat this virus.
The renin-angiotensin system has emerged as a key modulator of cardiomyopathies, with both local and central effects on the cardiac tissue. With the increase in incidences of cardiac disorders worldwide, the roles of the renin-angiotensin system on the cardiomyopathies have been revealed by scientists. Recent reports suggest that this system might regulate the synthesis of melatonin. This has drawn the interest of scientists globally since melatonin has remarkable protective effects on cardiomyopathies caused by atherosclerosis, cardiac ischemia, and myocardial infarction. Thus, understanding the interactions of melatonin with various components of the renin-angiotensin system becomes a necessary step for devising a targeted therapy for the various cardiomyopathies. This review has summarized the major effects of various components of the renin-angiotensin system on the cardiac tissue and the interaction of this system with melatonin. The role of melatonin in mediating cardioprotective effects by inhibition of certain components of this system has also been discussed.
Results obtained with the blood bathed organ technique indicate that angiotensin I is converted rapidly to angiotensin II in the pulmonary circulation and not by an enzyme in the blood.
Background Diabetes mellitus is a strong risk factor for cardiovascular and renal disease. We investigated whether the angiotensin-converting-enzyme (ACE) inhibitor ramipril can lower these risks in patients with diabetes. Methods 3577 people with diabetes included in the Heart Outcomes Prevention Evaluation study, aged 55 years or older, who had a previous cardiovascular event or at least one other cardiovascular risk factor, no clinical proteinuria, heart failure, or low ejection fraction, and who were not taking ACE inhibitors, were randomly assigned ramipril (10 mg/day) or placebo, and Vitamin E or placebo, according to a two-by-two factorial design. The combined primary outcome was myocardial infarction, stroke, or cardiovascular death. Overt nephropathy was a main outcome in a substudy. Findings The study was stopped 6 months early (after 4.5 years) by the independent data safety and monitoring board because of a consistent benefit of ramipril compared with placebo. Ramipril lowered the risk of the combined primary outcome by 25% (95% CI 12-36, p=0.0004), myocardial infarction by 22% (6-36), stroke by 33% (10-50), cardiovascular death by 37% (21-51), total mortality by 24% (8-37), revascularisation by 17% (2-30), and overt nephropathy by 24% (3-40, p=0.027). After adjustment for the changes in systolic (2.4 mm Hg) and diastolic (1.0 mm Hg) brood pressures, ramipril stilt lowered the risk of the combined primary outcome by 25% (12-36, p=0.0004). Interpretation Ramipril was beneficial for cardiovascular events and overt nephropathy in people with diabetes. The cardiovascular benefit was greater than that attributable to the decrease in blood pressure. This treatment represents a vasculoprotective and renoprotective effect for people with diabetes.
Survival after acute myocardial infarction has been enhanced by treatment with thrombolytic agents, aspirin, and beta-adrenoceptor blockade. However, there remains a substantial subgroup of patients who manifest clinical evidence of heart failure despite the first two of these treatments, and for whom beta-adrenoceptor antagonists are relatively or absolutely contraindicated. These patients have a greatly increased risk of fatal and non-fatal ischaemic, arrhythmic, and haemodynamic events. In this selected high-risk subset of patients we investigated the effect of therapy with the angiotensin converting enzyme (ACE) inhibitor ramipril, postulating that it would lengthen survival. 2006 patients who had shown clinical evidence of heart failure at any time after an acute myocardial infarction (AMI) were recruited from 144 centres in 14 countries. Patients were randomly allocated to double-blind treatment with either placebo (992 patients) or ramipril (1014 patients) on day 3 to day 10 after AMI (day 1). Patients with severe heart failure resistant to conventional therapy, in whom the attending physician considered the use of an ACE inhibitor to be mandatory, were excluded. Follow-up was continued for a minimum of 6 months and an average of 15 months. On intention-to-treat analysis mortality from all causes was significantly lower for patients randomised to receive ramipril (170 deaths; 17%) than for those randomised to receive placebo (222 deaths; 23%). The observed risk reduction was 27% (95% CI 11% to 40%; p=0.002). Analysis of prespecified secondary outcomes revealed a risk reduction of 19% for the first validated outcome (ie, first event in an individual patient)-namely, death, severe/resistant heart failure, myocardial infarction, or stroke (95% CI 5% to 31%; p=0.008). Oral administration of ramipril to patients with clinical evidence of either transient or ongoing heart failure, initiated between the second and ninth day after myocardial infarction, resulted in a substantial reduction in premature death from all causes. This benefit was apparent as early as 30 days and was consistent across a range of subgroups.
Angiotensin-receptor blockers (ARBs) are effective treatments for patients with heart failure, but the relation between dose and clinical outcomes has not been explored. We compared the effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure.
METHODS:
This double-blind trial was undertaken in 255 sites in 30 countries. 3846 patients with heart failure of New York Heart Association class II-IV, left-ventricular ejection fraction 40% or less, and intolerance to angiotensin-converting-enzyme (ACE) inhibitors were randomly assigned to losartan 150 mg (n=1927) or 50 mg daily (n=1919). Allocation was by block randomisation stratified by centre and presence or absence of beta-blocker therapy, and all patients and investigators were masked to assignment. The primary endpoint was death or admission for heart failure. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00090259.
FINDINGS:
Six patients in each group were excluded because of poor data quality. With 4.7-year median follow-up in each group (IQR 3.7-5.5 for losartan 150 mg; 3.4-5.5 for losartan 50 mg), 828 (43%) patients in the 150 mg group versus 889 (46%) in the 50 mg group died or were admitted for heart failure (hazard ratio [HR] 0.90, 95% CI 0.82-0.99; p=0.027). For the two primary endpoint components, 635 patients in the 150 mg group versus 665 in the 50 mg group died (HR 0.94, 95% CI 0.84-1.04; p=0.24), and 450 versus 503 patients were admitted for heart failure (0.87, 0.76-0.98; p=0.025). Renal impairment (n=454 vs 317), hypotension (203 vs 145), and hyperkalaemia (195 vs 131) were more common in the 150 mg group than in the 50 mg group, but these adverse events did not lead to significantly more treatment discontinuations in the 150 mg group.
INTERPRETATION:
Losartan 150 mg daily reduced the rate of death or admission for heart failure in patients with heart failure, reduced left-ventricular ejection fraction, and intolerance to ACE inhibitors compared with losartan 50 mg daily. These findings show the value of up-titrating ARB doses to confer clinical benefit.
FUNDING:
Merck (USA).
Background-Several large-scale trials have demonstrated improved survival with ACE-inhibitor therapy started during acute myocardial infarction. A systematic overview was conducted to resolve uncertainties regarding time of initiation, time course of effect, and identification of patients in whom the benefits or the risks may be greater. Methods and Results-This overview aimed to include individual data from all randomized trials involving more than 1000 patients in which ACE-inhibitor treatment was started in the acute phase (0 to 36 hours) of myocardial infarction and continued for a short time (4 to 6 weeks). Data were available for 98496 patients from 4 eligible trials, and the results were consistent among the trials. Thirty-day mortality was 7.1% among patients allocated to ACE inhibitors and 7.6% among control subjects, corresponding to a 7% (SD, 2%) proportional reduction (95% CI, 2% to 11%; 2P < 0.004). This represented avoidance of approximate to 5 (SD, 2) deaths per 1000 patients, with most of the benefit observed within the first week. The proportional benefit was similar in patients at different underlying risk. The absolute benefit was particularly large in some high-risk groups tie, Killip class 2 to 3, heart rate greater than or equal to 100 bpm at entry) and in anterior MI. ACE-inhibitor therapy also reduced the incidence of nonfatal cardiac failure (14.6% versus 15.2%, 2P = 0.01) but was associated with an excess of persistent hypotension (17.6% versus 9.3%, 2P < 0.01) and renal dysfunction (1.3% versus 0.6%, 2P < 0.01). Conclusions-These results support the use of ACE inhibitors early in the treatment of acute MI, either to a wide range of patients or selectively in patients with anterior MI and in those at increased risk of death.
Objectives. This 6-month follow-up analysis sought to assess whether the early reduction of mortality obtained with a 6-week treatment course of lisinopril or glyceryl trinitrate, or both, in unselected patients with acute myocardial infarction outlasts therapy and is still present after 6 months. The primary outcome of the 6-month follow up was the combined end point of mortality and severe left ventricular dysfunction. Background. The assumption was that the early benefit on remodeling processes may be maintained over a longer period of time, even in the absence of treatment. Methods. A total of 19,394 patients with acute myocardial infarction were randomized, within 24 h of onset of symptoms to a 6-week treatment course of oral lisinopril or open control and, according to a 2 x 2 factorial design, to glyceryl trinitrate or open control. Randomized treatments were stopped after 6 weeks in the absence of specific indications, and the patients were followed up for 6 months. Results. At 6 months, among patients randomized to lisinopril, 18.1% died or developed severe ventricular dysfunction versus 19.3% of those randomized to no lisinopril (2p = 0.03). No difference was found between patients with and without glyceryl trinitrate therapy (18.4% vs, 18.9%, 2p = 0.39). Conclusions. Although the systematic administration of glyceryl trinitrate started early and continued for 6 weeks after acute myocardial infarction does not yield evidence of benefit, early treatment with lisinopril appears to improve prognosis. This effect seems to carry over the first 6 months from randomization, even after treatment withdrawal.
In insulin-dependent diabetes mellitus (IDDM), microalbuminuria predicts renal and cardiovascular disease. We report a combined analysis of 235 normotensive IDDM patients with microalbuminuria who participated in two 24-month double-blind, randomised, placebo-controlled trials to assess the effects of captopril 50 mg twice daily on the progression to overt clinical albuminuria. Of the 225 patients who were evaluable on an intent to treat basis, 25 of 114 placebo-treated patients (21.9%) and 8 of 111 captopril-treated patients (7.2%) progressed to persistent clinical albuminuria. The risk of progression over 24 months was significantly reduced by captopril (p=0.004) with a risk reduction of 69.2% (95% confidence interval (CI): 31.7 to 86.1%). This degree of risk reduction remained at the same level (62.9% [16.1–83.6%], p=0.017) after adjustment for differences in time-varying mean arterial blood pressure. Albumin excretion rate increased by an average of 14.2% [3.1–26.5%] per year in the placebo-treated group compared with a reduction of 9.6% [−18.6–0.4%] per year in the captopril-treated group (p=0.002). The rate of fall of creatinine clearance tended to be faster in the placebo-treated group than in the captopril-treated group (−6.4 [−10.2–−2.5] vs −1.4 [−5.3–2.6] ml · min−1 · 1.73 m−2, p=0.07). Baseline albumin excretion rate (p<0.0001) and glycated haemoglobin (p=0.03) were independent predictors of progression to clinical albuminuria and changes in mean arterial blood pressure (p=0.02) and serum cholesterol level (p=0.003) were significantly associated with percentage changes in albumin excretion rate. Captopril reduces the risk of progression to overt nephropathy in IDDM patients with microalbuminuria, an effect partly independent of its blood pressure-lowering effects.
INTRODUCTION: CHRONIC KIDNEY disease (CKD) is a worldwide public health issue. In the United States, there is a rising incidence and prevalence of kidney failure (Fig 1), with poor outcomes and high cost. The prevalence of earlier stages of CKD is approximately 100 times greater than the prevalence of kidney failure, affecting almost 11% of adults in the United States. There is growing evidence that some of the adverse outcomes of CKD can be prevented or delayed by preventive measures, early detection, and treatment. Hypertension is a cause and complication of CKD. Hypertension in CKD increases the risk of important adverse outcomes, including loss of kidney function and kidney failure, early development and accelerated progression of cardiovascular disease (CVD), and premature death. In the ongoing effort to improve outcomes of CKD, the National Kidney Foundation (NKF) Kidney Disease Outcomes Quality Initiative (K/DOQI) appointed a Work Group and an Evidence Review Team in 2001 to develop clinical practice guidelines on hypertension and use of antihypertensive agents in CKD. During this same time, clinical practice guidelines on this topic relevant to CKD were also under development by other organizations, including the Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) and the 2003 report of the American Diabetes Association (ADA) on the Treatment of Hypertension in Adults with Diabetes. The Work Group maintained contact with these organizations during development of these guidelines. The purpose of the Executive Summary is to provide a "stand-alone" summary of the background, scope, methods, and key recommendations, as well as the complete text of the guideline statements. Most tables and figures in the Executive Summary are taken from other sections of the document. BACKGROUND: Chronic Kidney Disease: Figure 2 is a conceptual model of CKD, which defines stages of CKD, as well as antecedent conditions, outcomes, risk factors for adverse outcomes, and actions to improve outcomes. CKD is defined as kidney damage, as confirmed by kidney biopsy or markers of damage, or glomerular filtration rate (GFR) <60 mL/min/1.73 m2 for ≥3 months (Table 1). Markers of kidney damage include proteinuria, abnormalities on the urine dipstick or sediment examination, or abnormalities on imaging studies of the kidneys. GFR can be estimated from prediction equations based on serum creatinine and other variables, including age, sex, race, and body size. Among individuals with CKD, the stage of disease is based on the level of GFR (Table 2), irrespective of the cause of kidney disease. The high prevalence of earlier stages of CKD emphasizes the importance for all health-care providers, not just kidney disease specialists, to detect, evaluate, and treat CKD. Hypertension in CKD: JNC 7 defines hypertension as systolic blood pressure (SBP) ≥140 mm Hg or diastolic blood pressure (DBP) ≥90 mm Hg, respectively (Table 3). Although common in CKD, hypertension is not part of the definition of CKD. Table 4 illustrates the classification of individuals based on presence or absence of kidney damage and hypertension, and level of GFR. Approximately 50% to 75% of individuals with GFR <60 mL/min/1.73 m2 (CKD Stages 3-5) have hypertension (Fig 3). Among individuals with GFR ≥60 mL/min/1.73 m 2, distinguishing CKD Stages 1 and 2 (Table 4, shaded areas) from "hypertension" and "hypertension with decreased GFR" (Table 4, unshaded areas) requires assessment for markers of kidney damage. This is especially important in the elderly, in whom both hypertension and decreased GFR are common. Cardiovascular Disease in CKD: CKD is a risk factor for cardiovascular disease (CVD). Dialysis patients have a 50 to 500 times increased risk of CVD mortality compared to age-matched individuals from the general population (Fig 4). Earlier stages of CKD are also associated with an increased risk of CVD. CKD is associated with an increased prevalence and severity of both "traditional" and "nontraditional" risk factors for CVD. Traditional risk factors include those initially described in the Framingham Study. Among traditional risk factors, hypertension is closely linked to CKD and has often been implicated as the main cause of CVD in CKD. Other traditional risk factors for CVD that are common in CKD include older age, diabetes and hyperlipidemia. Nontraditional risk factors for CVD such as inflammation, malnutrition, mineral disorders (calcium and phosphorus), and anemia are also common in CKD. In addition, albuminuria (Fig 5) and decreased GFR (Fig 6) are associated with an increased risk of CVD, even after controlling for many of these risk factors. Early detection and treatment of CKD, including detection and treatment of hypertension and other CVD risk factors, may reduce the risk of CVD in CKD. Achieving these goals in CKD will require coordinating antihyper tensive therapy with therapy for other CVD risk factors. Recommendations for antihypertensive therapy in the general population are based on observational studies and controlled trials relating blood pressure level and antihypertensive therapy to CVD risk. Few patients with CKD were included in these studies. Thus, recommendations to reduce CVD risk in CKD are based largely on extrapolation from the general population. Progression of CKD: Most kidney diseases worsen progressively over time. Antihypertensive therapy affects several modifiable key factors related to the progression of kidney disease, including hypertension, proteinuria, and other mechanisms, such as increased activity of the renin-angiotensin system (RAS) (Fig 7). Several large, controlled trials have examined the effect of antihypertensive therapy on the progression of kidney disease in patients with and without hypertension. While these trials have provided important answers about therapy, the relationships among these "progression factors" are complex, and many questions remain unanswered, especially regarding the mechanisms underlying the therapeutic benefit of the interventions. Based on these considerations, the Work Group defined the following goals for antihypertensive therapy in CKD (Table 5) and strategies and therapeutic targets to achieve them (Table 6). This formulation is consistent with the JNC 7 report, which recommends lifestyle modifications and pharmacological therapy to lower blood pressure and reduce CVD risk, with modifications for "compelling indications," including CKD. As indicated in Table 6, the Work Group recommended that clinicians consider reducing proteinuria as a goal for antihypertensive therapy in CKD. Proteinuria is important in CKD for a number of reasons (Table 7). There is strong evidence that proteinuria is a marker of kidney damage, and its presence identifies individuals with CKD. Large amounts of proteinuria are a clue to the type (diagnosis) of CKD. Higher levels of proteinuria are a risk factor for faster progression of CKD and development of CVD. Higher levels of proteinuria also identify individuals who benefit more from antihypertensive therapy. However, the Work Group decided that the evidence is not strong enough to conclude that proteinuria is a surrogate outcome for kidney disease progression. However, it was the opinion of the Work Group that proteinuria should be monitored during the course of CKD, and that under some circumstances, it would be appropriate to consider modifications to the antihypertensive regimen in patients with large amounts of proteinuria, such as a lower blood pressure goal or measures to reduce proteinuria. In general, these modifications should be undertaken in consultation with a nephrologist. The Work Group strongly recommended further research on this topic. SCOPE OF THE GUIDELINES: The Work Group was convened by the NKF Kidney Disease Outcomes Quality Initiative (K/DOQI) in response to recommendations of the NKF Task Force on CVD (Fig 8). The overall aim of the Work Group was to develop evidence-based recommendations for the evaluation and management of hypertension and use of antihypertensive agents in CKD. Topics considered are listed in Table 8. Based on the results of clinical and epidemiological studies, the Work Group defined the target population for these guidelines as patients with CKD Stages 1-4. Patients with CKD Stage 5 (kidney failure) were excluded since kidney disease progression may not be as important in patients who have already reached the stage of kidney failure, because the relationship between CVD risk and level of blood pressure is complex in kidney failure, and because of intermittent fluid shifts that affect blood pressure in hemodialysis patients. Thus, the Work Group concluded that the evidence base was not sufficient to develop strong recommendations for patients with kidney failure, and that extrapolation from the general population or from populations with earlier stages of CKD to those with kidney failure may not be appropriate. The Work Group acknowledges the importance of this topic, which will be addressed in a forthcoming K/DOQI Clinical Practice Guideline. The Work Group has included recommendations for both adults and children. Guideline 13 for children was written with careful consideration of past recommendations for the treatment of hypertension in children by JNC reports and by the National High Blood Pressure Education Program Work Group for Children and Adolescents. Two topics are highlighted in the Guidelines in which evidence is rapidly accumulating, but the evidence base is not yet sufficient for strong or moderately strong recommendations: use of ambulatory blood pressure monitoring (Guideline 3 and Appendix 3) and additional interventions for patients with large amounts of proteinuria (Background, Guidelines 1, 8-11).
Background.
It is not known whether the treatment of patients with asymptomatic left ventricular dysfunction reduces mortality and morbidity. We studied the effect of an angiotensin-converting—enzyme inhibitor, enalapril, on total mortality and mortality from cardiovascular causes, the development of heart failure, and hospitalization for heart failure among patients with ejection fractions of 0.35 or less who were not receiving drug treatment for heart failure.
Methods.
Patients were randomly assigned to receive either placebo (n = 2117) or enalapril (n = 2111) at doses of 2.5 to 20 mg per day in a double-blind trial. Follow-up averaged 37.4 months.
Results.
There were 334 deaths in the placebo group, as compared with 313 in the enalapril group (reduction in risk, 8 percent by the log-rank test; 95 percent confidence interval, -8 percent [an increase of 8 percent] to 21 percent; P = 0.30). The reduction in mortality from cardiovascular causes was larger but was not statistically significant (298 deaths in the placebo group vs. 265 in the enalapril group; risk reduction, 12 percent; 95 percent confidence interval, -3 to 26 percent; P = 0.12). When we combined patients in whom heart failure developed and those who died, the total number of deaths and cases of heart failure was lower in the enalapril group than in the placebo group (630 vs. 818; risk reduction, 29 percent; 95 percent confidence interval, 21 to 36 percent; P<0.001). In addition, fewer patients given enalapril died or were hospitalized for heart failure (434 in the enalapril group vs. 518 in the placebo group; risk reduction, 20 percent; 95 percent confidence interval, 9 to 30 percent; P<0.001).
Conclusions.
The angiotensin-converting—enzyme inhibitor enalapril significantly reduced the incidence of heart failure and the rate of related hospitalizations, as compared with the rates in the group given placebo, among patients with asymptomatic left ventricular dysfunction. There was also a trend toward fewer deaths due to cardiovascular causes among the patients who received enalapril. (N Engl J Med 1992;327:685–91.)
For several years the European Society of Hypertension (ESH) and the European Society of Cardiology (ESC) decided not to produce their own guidelines on the diagnosis and treatment of hypertension but to endorse the guidelines on hypertension issued by the World Health Organization (WHO) and International Society of Hypertension (ISH)1,2 with some adaptation to reflect the situation in Europe. However, in 2003 the decision was taken to publish ESH/ESC specific guidelines3 based on the fact that, because the WHO/ISH Guidelines address countries widely varying in the extent of their health care and availability of economic resource, they contain diagnostic and therapeutic recommendations that may be not totally appropriate for European countries. In Europe care provisions may often allow a more in-depth diagnostic assessment of cardiovascular risk and organ damage of hypertensive individuals as well as a wider choice of antihypertensive treatment.
The 2003 ESH/ESC Guidelines3 were well received by the clinical world and have been the most widely quoted paper in the medical literature in the last two years.4 However, since 2003 considerable additional evidence on important issues related to diagnostic and treatment approaches to hypertension has become available and therefore updating of the previous guidelines has been found advisable.
In preparing the new guidelines the Committee established by the ESH and ESC has agreed to adhere to the principles informing the 2003 Guidelines, namely 1) to try to offer the best available and most balanced recommendation to all health care providers involved in the management of hypertension, 2) to address this aim again by an extensive and critical review of the data accompanied by a series of boxes where specific recommendations are given, as well as by a concise set of practice recommendations to be published soon thereafter as already done in 2003; …
Background.
Patients with congestive heart failure have a high mortality rate and are also hospitalized frequently. We studied the effect of an angiotensin-converting—enzyme inhibitor, enalapril, on mortality and hospitalizaron in patients with chronic heart failure and ejection fractions ≤0.35.
Methods.
Patients receiving conventional treatment for heart failure were randomly assigned to receive either placebo (n = 1284) or enalapril (n = 1285) at doses of 2.5 to 20 mg per day in a double-blind trial. Approximately 90 percent of the patients were in New York Heart Association functional classes II and III. The follow-up averaged 41.4 months.
Results.
There were 510 deaths in the placebo group (39.7 percent), as compared with 452 in the enalapril group (35.2 percent) (reduction in risk, 16 percent; 95 percent confidence interval, 5 to 26 percent; P = 0.0036). Although reductions in mortality were observed in several categories of cardiac deaths, the largest reduction occurred among the deaths attributed to progressive heart failure (251 in the placebo group vs. 209 in the enalapril group; reduction in risk, 22 percent; 95 percent confidence interval, 6 to 35 percent). There was little apparent effect of treatment on deaths classified as due to arrhythmia without pump failure. Fewer patients died or were hospitalized for worsening heart failure (736 in the placebo group and 613 in the enalapril group; risk reduction, 26 percent; 95 percent confidence interval, 18 to 34 percent; P<0.0001).
Conclusions.
The addition of enalapril to conventional therapy significantly reduced mortality and hospitalizations for heart failure in patients with chronic congestive heart failure and low ejection fractions. (N Engl J Med 1991; 325:293–302.)
Background Treatment with angiotensin-converting-enzyme (ACE) inhibitors reduces the rate of cardiovascular events among patients with left-ventricular dysfunction and those at high risk of such events. We assessed whether the ACE inhibitor perindopril reduced cardiovascular risk in a low-risk population with stable coronary heart disease and no apparent heart failure. Methods We recruited patients from October, 1997, to June, 2000. 13 655 patients were registered with previous myocardial infarction (64%), angiographic evidence of coronary artery disease (61%), coronary revascularisation (55%), or a positive stress test only (5%). After a run-in period of 4 weeks, in which all patients received perindopril, 12 218 patients were randomly assigned perindopril 8 mg once daily (n=6110), or matching placebo (n=6108). The mean follow-up was 4.2 years, and the primary endpoint was cardiovascular death, myocardial infarction, or cardiac arrest. Analysis was by intention to treat. Findings Mean age of patients was 60 years (SD 9), 85% were male, 92% were taking platelet inhibitors, 62% beta blockers, and 58% lipid-lowering therapy. 603 (10%) placebo and 488 (8%) perindopril patients experienced the primary endpoint, which yields a 20% relative risk reduction (95% CI 9-29, p=0.0003) with perindopril. These benefits were consistent in all predefined subgroups and secondary endpoints. Perindopril was well tolerated. Interpretation Among patients with stable coronary heart disease without apparent heart failure, perindopril can significantly improve outcome. About 50 patients need to be treated for a period of 4 years to prevent one major cardiovascular event. Treatment with perindopril, on top of other preventive medications, should be considered in all patients with coronary heart disease.
To evaluate the influence of the angiotensin-converting-enzyme inhibitor enalapril (2.5 to 40 mg per day) on the prognosis of severe congestive heart failure (New York Heart Association [NYHA] functional class IV), we randomly assigned 253 patients in a double-blind study to receive either placebo (n = 126) or enalapril (n = 127). Conventional treatment for heart failure, including the use of other vasodilators, was continued in both groups. Follow-up averaged 188 days (range, 1 day to 20 months). The crude mortality at the end of six months (primary end point) was 26 percent in the enalapril group and 44 percent in the placebo group - a reduction of 40 percent (P = 0.002). Mortality was reduced by 31 percent at one year (P = 0.001). By the end of the study, there had been 68 deaths in the placebo group and 50 in the enalapril group - a reduction of 27 percent (P = 0.003). The entire reduction in total mortality was found to be among patients with progressive heart failure (a reduction of 50 percent), whereas no difference was seen in the incidence of sudden cardiac death. A significant improvement in NYHA classification was observed in the enalapril group, together with a reduction in heart size and a reduced requirement for other medication for heart failure. The overall withdrawal rate was similar in both groups, but hypotension requiring withdrawal occurred in seven patients in the enalapril group and in no patients in the placebo group. After the initial dose of enalapril was reduced to 2.5 mg daily in high-risk patients, this side effect was less frequent. We conclude that the addition of enalapril to conventional therapy in patients with severe congestive heart failure can reduce mortality and improve symptoms. The beneficial effect on mortality is due to a reduction in death from the progression of heart failure.
Background:
This programme of overviews of randomised trials was established to investigate the effects of angiotensin-converting-enzyme (ACE) inhibitors, calcium antagonists, and other blood-pressure-lowering drugs on mortality and major cardiovascular morbidity in several populations of patients. We did separate overviews of trials comparing active treatment regimens with placebo, trials comparing more intensive and less intensive blood-pressure-lowering strategies, and trials comparing treatment regimens based on different drug classes.
Methods:
The hypotheses to be investigated, the trials to be included, and the outcomes to be studied were all selected before the results of any participating trial were known. Individual participant data or group tabular data were provided by each trial and combined by standard statistical techniques.
Findings:
The overview of placebo-controlled trials of ACE inhibitors (four trials, 12,124 patients mostly with coronary heart disease) revealed reductions in stroke (30% [95% CI 15-43]), coronary heart disease (20% [11-28]), and major cardiovascular events (21% [14-27]). The overview of placebo-controlled trials of calcium antagonists (two trials, 5520 patients mostly with hypertension) showed reductions in stroke (39% [15-56]) and major cardiovascular events (28% [13-41]). In the overview of trials comparing blood-pressure-lowering strategies of different intensity (three trials, 20,408 patients with hypertension), there were reduced risks of stroke (20% [2-35]), coronary heart disease (19% [2-33]), and major cardiovascular events (15% [4-24]) with more intensive therapy. In the overviews comparing different antihypertensive regimens (eight trials, 37,872 patients with hypertension), several differences in cause-specific effects were seen between calcium-antagonist-based therapy and other regimens, but each was of borderline significance.
Interpretation:
Strong evidence of benefits of ACE inhibitors and calcium antagonists is provided by the overviews of placebo-controlled trials. There is weaker evidence of differences between treatment regimens of differing intensities and of differences between treatment regimens based on different drug classes. Data from continuing trials of blood-pressure-lowering drugs will substantially increase the evidence available about any real differences that might exist between regimens.
GISSI-3 is a multicentre randomised clinical trial to assess the efficacy of lisinopril, transdermal glyceryl trinitrate (GTN), and their combination in improving survival and ventricular function after acute myocardial infarction (AMI). Between June, 1991, and July, 1993, 19 394 patients were randomised from 200 coronary care units in Italy. Eligible patients presented within 24 h of symptom onset and had no clear indications for or against the study treatments. In a factorial design patients were randomly assigned 6 weeks of oral lisinopril (5 mg initial dose and then 10 mg daily) or open control as well as nitrates (intravenous for the first 24 h followed by transdermal GTN 10 mg daily) or open control. Complete clinical data and 6-week follow-up were available for 18 895 (97.4%) patients randomised. Two-dimensional echocardiographic data were available for 14 209 patients. Overall 6-week mortality was 6.7%. Lisinopril, started within 24 h from AMI symptoms, produced significant reductions in overall mortality (odds ratio 0.88 [95% CI 0.79-0.99]) and in the combined outcome measure of mortality and severe ventricular dysfunction (0.90 [0.84-0.98]). In the same trial the systematic administration of transdermal GTN did not show any independent effect on the same outcome measures (0.94 [0.84-1.05] and 0.94 [0.87-1.02]). Systematic combined administration of lisinopril and GTN also produced significant reductions in overall mortality (0.83 [0.70-0.97]) and in the combined endpoint (0.85 [0.76-0.94]). The favourable effect of lisinopril alone or with GTN was clear also in the predefined high-risk populations (elderly patients and women) for the combined endpoint. These findings were obtained in a population intensively exposed to recommended treatments (thrombolysis 72%, beta-blockade 31%, and aspirin 84%); non-protocol treatment with angiotensin-converting-enzyme inhibitors and nitrates was allowed for specific clinical indications. No excess of unfavourable clinically relevant events in the treated groups was reported.
Background Blood pressure is a determinant of the risk of stroke among both hypertensive and non-hypertensive individuals with cerebrovascular disease. However, there is uncertainty about the efficacy and safety of blood-pressure-lowering treatments for many such patients. The perindopril protection against recurrent stroke study (PROGRESS) was designed to determine the effects of a blood-pressure-lowering regimen in hypertensive and non-hypertensive patients with a history of stroke or transient ischaemic attack. Methods 6105 individuals from 172 centres in Asia, Australasia, and Europe were randomly assigned active treatment (n = 3051) or placebo (n = 3054). Active treatment comprised a flexible regimen based on the angiotensin-converting-enzyme inhibitor perindopril (4 mg daily), with the addition of the diuretic indapamide at the discretion of treating physicians. The primary outcome was total stroke (fatal or non-fatal). Analysis was by intention to treat. Findings Over 4 years of follow up, active treatment reduced blood pressure by 9/4 mm Hg. 307 (10%) individuals assigned active treatment suffered a stroke, compared with 420 (14%) assigned placebo (relative risk reduction 28% [95% Cl 17-38], p < 0.0001). Active treatment also reduced the risk of total major vascular events (26% [16-34]). There were similar reductions in the risk of stroke in hypertensive and non-hypertensive subgroups (all p < 0.01). Combination therapy with perindopril plus indapamide reduced blood pressure by 12/5 mm Hg and stroke risk by 43% (30-54). Single-drug therapy reduced blood pressure by 5/3 mm Hg and produced no discernable reduction in the risk of stroke. Interpretation This blood-pressure-lowering regimen reduced the risk of stroke among both hypertensive and nonhypertensive individuals with a history of stroke or transient ischaemic attack. Combination therapy with perindopril and indapamide produced larger blood pressure reductions and larger risk reductions than did single drug therapy with perindopril alone. Treatment with these two agents should now be considered routinely for patients with a history of stroke or transient ischaemic attack, irrespective of their blood pressure.
Two types of hypertensin have been demonstrated by means of counter-current distribution. The first type is the product of the action of the enzyme, renin, upon its substrate and has been designated hypertensin I. It can be rapidly converted to a second approximately equally pressor compound, hypertensin II, apparently through the action of an enzyme in the plasma which requires halide or nitrate for activation.
A highly purified preparation containing horse hypertensins I and II caused an elevation of blood pressure when injected into human beings.
The incidence of congestive heart failure is increasing in the United States. This common syndrome is characterized not only by impaired ventricular function but also by an increase in some endogenous vasoconstrictor substances, including norepinephrine, angiotensin II, and arginine vasopressin. Although activation of the systems that release these substances is presumed to be compensatory (to maintain perfusion pressure during inadequate flow), the sympathetic nervous system, renin-angiotensin-aldosterone system, and arginine vasopressin may contribute to the pathogenesis of the syndrome. The excessive vasoconstriction present in heart failure likely produces a further burden on the failing myocardium. New strategies in therapy are being developed to counteract the activation of vasoconstrictor forces in congestive heart failure. Data indicate that selective blockade of the reninangiotensin system is useful. Preliminary data suggest that inhibition of the sympathetic nervous system may be helpful, and inhibition of vasopressin in animals with heart failure is being studied. New and more selective therapy for heart failure may come from these studies.
58,050 patients entering 1086 hospitals up to 24 h (median 8 h) after the onset of suspected acute myocardial infarction (MI) with no clear contraindications to the study treatments (in particular, no cardiogenic shock or persistent severe hypotension) were randomised in a "2 x 2 x 2 factorial" study. The treatment comparisons were: (i) 1 month of oral captopril (6.25 mg initial dose titrated up to 50 mg twice daily) versus matching placebo; (ii) 1 month of oral controlled-release mononitrate (30 mg initial dose titrated up to 60 mg once daily) versus matching placebo; and (iii) 24 h of intravenous magnesium sulphate (8 mmol initial bolus followed by 72 mmol) versus open control. There were no significant "interactions" between the effects of these three treatments, and the results for each are based on the randomised comparison of about 29,000 active versus 29,000 control allocated patients. Captopril There was a significant 7% (SD 3) proportional reduction in 5-week mortality (2088 [7.19%] captopril-allocated deaths vs 2231 [7.69%] placebo; 2p = 0.02), which corresponds to an absolute difference of 4.9 SD 2.2 fewer deaths per 1000 patients treated for 1 month. The absolute benefits appeared to be larger (perhaps about 10 fewer deaths per 1000) in certain higher-risk groups, such as those presenting with a history of previous MI or with heart failure. The survival advantage appeared to be maintained in the longer term (5.4 [SD 2.8] fewer deaths per 1000 at 12 months). Captopril was associated with an increase of 52 (SD 2) patients per 1000 in hypotension considered severe enough to require termination of study treatment, of 5 (SD 2) per 1000 in reported cardiogenic shock, and of 5 (SD 1) per 1000 in some degree of renal dysfunction. It produced no excess of deaths on days 0-1, even among patients with low blood pressure at entry. Mononitrate There was no significant reduction in 5-week mortality, either overall (2129 [7.34%] mononitrate-allocated deaths vs 2190 [7.54%] placebo) or in any subgroup examined (including those receiving short-term non-study intravenous or oral nitrates at entry). Further follow-up did not indicate any later survival advantage. The only significant side-effect of the mononitrate regimen studied was an increase of 15 (SD 2) per 1000 in hypotension. Those allocated active treatment had somewhat fewer deaths on days 0-1, which is reassuring a bout the safety of using nitrates early in acute MI.(ABSTRACT TRUNCATED AT 400 WORDS)
GISSI-3 is a multicentre randomised clinical trial to assess the efficacy of lisinopril, transdermal glyceryl trinitrate (GTN), and their combination in improving survival and ventricular function after acute myocardial infarction (AMI). Between June, 1991, and July, 1993, 19,394 patients were randomised from 200 coronary care units in Italy. Eligible patients presented within 24 h of symptom onset and had no clear indications for or against the study treatments. In a factorial design patients were randomly assigned 6 weeks of oral lisinopril (5 mg initial dose and then 10 mg daily) or open control as well as nitrates (intravenous for the first 24 h followed by transdermal GTN 10 mg daily) or open control. Complete clinical data and 6-week follow-up were available for 18,895 (97.4%) patients randomised. Two-dimensional echocardiographic data were available for 14,209 patients. Overall 6-week mortality was 6.7%. Lisinopril, started within 24 h from AMI symptoms, produced significant reductions in overall mortality (odds ratio 0.88 [95% CI 0.79-0.99]) and in the combined outcome measure of mortality and severe ventricular dysfunction (0.90 [0.84-0.98]). In the same trial the systematic administration of transdermal GTN did not show any independent effect on the same outcome measures (0.94 [0.84-1.05] and 0.94 [0.87-1.02]). Systematic combined administration of lisinopril and GTN also produced significant reductions in overall mortality (0.83 [0.70-0.97]) and in the combined endpoint (0.85 [0.76-0.94]). The favourable effect of lisinopril alone or with GTN was clear also in the predefined high-risk populations (elderly patients and women) for the combined endpoint. These findings were obtained in a population intensively exposed to recommended treatments (thrombolysis 72%, beta-blockade 31%, and aspirin 84%); non-protocol treatment with angiotensin-converting-enzyme inhibitors and nitrates was allowed for specific clinical indications. No excess of unfavourable clinically relevant events in the treated groups was reported.
Background:
Several large-scale trials have demonstrated improved survival with ACE-inhibitor therapy started during acute myocardial infarction. A systematic overview was conducted to resolve uncertainties regarding time of initiation, time course of effect, and identification of patients in whom the benefits or the risks may be greater.
Methods and results:
This overview aimed to include individual data from all randomized trials involving more than 1000 patients in which ACE-inhibitor treatment was started in the acute phase (0 to 36 hours) of myocardial infarction and continued for a short time (4 to 6 weeks). Data were available for 98,496 patients from 4 eligible trials, and the results were consistent among the trials. Thirty-day mortality was 7.1% among patients allocated to ACE inhibitors and 7.6% among control subjects, corresponding to a 7% (SD, 2%) proportional reduction (95% CI, 2% to 11%; 2P<0.004). This represented avoidance of approximately 5 (SD, 2) deaths per 1000 patients, with most of the benefit observed within the first week. The proportional benefit was similar in patients at different underlying risk. The absolute benefit was particularly large in some high-risk groups (ie, Killip class 2 to 3, heart rate > or = 100 bpm at entry) and in anterior MI. ACE-inhibitor therapy also reduced the incidence of nonfatal cardiac failure (14.6% versus 15.2%, 2P=0.01) but was associated with an excess of persistent hypotension (17.6% versus 9.3%, 2P<0.01) and renal dysfunction (1.3% versus 0.6%, 2P<0.01).
Conclusions:
These results support the use of ACE inhibitors early in the treatment of acute MI, either to a wide range of patients or selectively in patients with anterior MI and in those at increased risk of death.
Objectives.
—To study the effect of angiotensin converting enzyme inhibition on the rate of progression to clinical proteinuria and the rate of change of albumin excretion rates in patients with insulin-dependent diabetes mellitus and persistent microalbuminuria.Design and Setting.
—Randomized, double-blind, placebo-controlled clinical trial of 2 years' duration at 12 hospital-based diabetes centers.Patients.
—Ninety-two patients with insulin-dependent diabetes mellitus and persistent microalbuminuria but no hypertension.Intervention.
—The patients were randomly allocated in blocks of two to receive either captopril, 50 mg, or placebo twice per day.Measurements.
—Albumin excretion rate, blood pressure, glycosylated hemoglobin level, and fructosamine level every 3 months; urinary urea nitrogen excretion every 6 months; and glomerular filtration rate every 12 months.Results.
—Twelve patients receiving placebo and four receiving captopril progressed to clinical proteinuria, defined as an albumin excretion rate persistently greater than 200 μg/min and at least a 30% increase from baseline (P=.05). The probability of progression to clinical proteinuria was significantly reduced by captopril therapy (P=.03 by log-rank test). Albumin excretion rate rose from a geometric mean (95% confidence interval) of 52 (39 to 68) to 76 (47 to 122) μg/min in the placebo group but fell from 52 (41 to 65) to 41 (28 to 60) μg/min in the captopril group, a significant difference (P<.01). Mean blood pressure was similar at baseline in the two groups and remained unchanged in the placebo group but fell significantly, by 3 to 7 mm Hg, in the captopril group. Glycosylated hemoglobin levels and glomerular filtration rate remained stable in the two groups.Conclusions.
—Captopril therapy significantly impeded progression to clinical proteinuria and prevented the increase in albumin excretion rate in nonhypertensive patients with insulin-dependent diabetes mellitus and persistent microalbuminuria.(JAMA. 1994;271:275-279)
Background: The prognostic benefits of blood pressure lowering treatment in elderly hypertensive patients were established more than a decade ago, but are less clear in those with mildly to moderately elevated blood pressure. Objective: To assess whether candesartan-based antihypertensive treatment in elderly patients with mildly to moderately elevated blood pressure confers a reduction in cardiovascular events, cognitive decline and dementia. Design: Prospective, double-blind, randomized, parallel-group study conducted in 1997–2002. Setting and participants: The study was of 4964 patients aged 70–89 years, with systolic blood pressure 160–179 mmHg, and/or diastolic blood pressure 90–99 mmHg, and a Mini Mental State Examination (MMSE) test score ≥ 24. A total of 527 centres in 15 countries participated in the study. Intervention: Patients were assigned randomly to receive the angiotensin receptor blocker candesartan or placebo, with open-label active antihypertensive therapy added as needed. As a consequence, active antihypertensive therapy was extensively used in the control group (84% of patients). Mean follow-up was 3.7 years. Main outcome measures: The primary outcome measure was major cardiovascular events, a composite of cardiovascular death, non-fatal stroke and non-fatal myocardial infarction. Secondary outcome measures included cardiovascular death, non-fatal and fatal stroke and myocardial infarction, cognitive function measured by the MMSE and dementia. Results: Blood pressure fell by 21.7/10.8 mmHg in the candesartan group and by 18.5/9.2 mmHg in the control group. A first major cardiovascular event occurred in 242 candesartan patients and in 268 control patients; risk reduction with candesartan was 10.9% [95% confidence interval (CI), −6.0 to 25.1, P = 0.19]. Candesartan-based treatment reduced non-fatal stroke by 27.8% (95% CI, 1.3 to 47.2, P = 0.04), and all stroke by 23.6% (95% CI, −0.7 to 42.1, P = 0.056). There were no significant differences in myocardial infarction and cardiovascular mortality. Mean MMSE score fell from 28.5 to 28.0 in the candesartan group and from 28.5 to 27.9 in the control group (P = 0.20). The proportions of patients who had a significant cognitive decline or developed dementia were not different in the two treatment groups. Conclusions: In elderly hypertensive patients, a slightly more effective blood pressure reduction during candesartan-based therapy, compared with control therapy, was associated with a modest, statistically non-significant, reduction in major cardiovascular events and with a marked reduction in non-fatal stroke. Cognitive function was well maintained in both treatment groups in the presence of substantial blood pressure reductions. Both treatment regimens were generally well tolerated.
Background: The role of angiotensin-receptor blockers (ARBs) in treating patients with chronic heart failure and high-risk acute myocardial infarction (MI) has been controversial, and recent clin- ical trials provide more information on this topic. Purpose: To quantify the effect of ARBs when compared with placebo (with and without background angiotensin-converting en- zyme (ACE) inhibitors) and ACE inhibitors on all-cause mortality and heart failure hospitalizations in patients with chronic heart failure and high-risk acute MI. (OR), 0.83 (95% CI, 0.69 to 1.00)) and heart failure hospitaliza- tions (OR, 0.64 (CI, 0.53 to 0.78)) as compared with placebo; 2) for ARBs versus ACE inhibitors, all-cause mortality (OR, 1.06 (CI, 0.90 to 1.26)) and heart failure hospitalization (OR, 0.95 (CI, 0.80 to 1.13)) did not differ; 3) and for combinations of ARBs plus ACE inhibitors versus ACE inhibitors alone, all-cause mortality was not reduced (OR, 0.97 (CI, 0.87 to 1.08)) but heart failure hospital- izations were reduced (OR, 0.77 (CI, 0.69 to 0.87)). For patients with high-risk acute MI, 2 randomized trials compared ARBs with ACE inhibitors but did not reveal differences in all-cause mortality or heart failure hospitalization. Limitations: Comparative economic data between ARBs and ACE inhibitors are lacking. Conclusions: Because ACE inhibitors and ARBs do not differ in efficacy for reducing all-cause mortality and heart failure hospital- izations in patients with chronic heart failure and in patients with high-risk acute MI, ARBs should be regarded as suitable alterna- tives to ACE inhibitors.
Blood pressure is a determinant of the risk of stroke among both hypertensive and non-hypertensive individuals with cerebrovascular disease. However, there is uncertainty about the efficacy and safety of blood-pressure-lowering treatments for many such patients. The perindopril protection against recurrent stroke study (PROGRESS) was designed to determine the effects of a blood-pressure-lowering regimen in hypertensive and non-hypertensive patients with a history of stroke or transient ischaemic attack.
Summary Background Angiotensin-converting-enzyme (ACE) inhibitors improve outcome of patients with chronic heart failure (CHF). A substantial proportion of patients, however, experience no benefit from ACE inhibitors because of previous intolerance. We aimed to find out whether candesartan, an angiotensinreceptor blocker, could improve outcome in such patients not taking an ACE inhibitor. Methods Between March, 1999, and March, 2001, we enrolled 2028 patients with symptomatic heart failure and left-ventricular ejection fraction 40% or less who were not receiving ACE inhibitors because of previous intolerance. Patients were randomly assigned candesartan (target dose 32 mg once daily) or matching placebo. The primary outcome of the study was the composite of cardiovascular death or hospital admission for CHF. Analysis was by intention to treat. Findings The most common manifestation of ACE-inhibitor intolerance was cough (72%), followed by symptomatic hypotension (13%) and renal dysfunction (12%). During a median follow-up of 33·7 months, 334 (33%) of 1013 patients in the candesartan group and 406 (40%) of 1015 in the placebo group had cardiovascular death or hospital admission for CHF (unadjusted hazard ratio 0·77 [95% CI 0·67–0·89], p=0·0004; covariate adjusted 0·70 [0·60–0·81], p<0·0001). Each component of the primary outcome was reduced, as was the total number of hospital admissions for CHF. Study-drug discontinuation rates were similar in the candesartan (30%) and placebo (29%) groups. Interpretation Candesartan was generally well tolerated and reduced cardiovascular mortality and morbidity in patients with symptomatic chronic heart failure and intolerance to ACE inhibitors.
Background: Heart failure in blacks has been associated with a poorer prognosis than in whites. In such diseases as hypertension, blacks show pathophysiological differences and respond differently to some therapies than whites. The aim of this study is to evaluate the clinical characteristics and response to therapy of black compared with white patients with heart failure.Methods and Results: In the first Vasodilator-Heart Failure Trial (V-HeFT I), 180 black male patients were compared with 450 white male patients for baseline characteristics, prognosis, and response to therapy. In V-HeFT II, the same comparisons were made for 215 black and 574 white male patients, including an analysis stratified by the presence or absence of a history of hypertension. In both trials, black patients had a lower incidence of coronary artery disease, greater incidence of previous hypertension, and a greater cardiothoracic ratio (P < .05) than white patients. In V-HeFT II, plasma norepinephrine levels were significantly less in blacks; plasma renin activity was less only in blacks with a history of hypertension. Overall mortality or hospitalization for congestive heart failure did not differ between blacks and whites in the placebo group in V-HeFT I. However, the mortality of black patients receiving hydralazine plus isosorbide dinitrate (H-I) was reduced (P = .04) in V-HeFT I, whereas white patients showed no difference from placebo. In V-HeFT II, only white patients showed a mortality reduction from enalapril therapy compared with H-I therapy (P = .02). Whites also showed evidence of greater blood pressure reduction and enhanced regression of cardiac size in response to enalapril. When stratified by history of hypertension in V-HeFT II, only whites with a history of hypertension, who had greater renin levels, showed significant mortality reduction with enalapril compared with H-I therapy. Hospitalization rates did not differ between treatment groups in either study.Conclusion: Whites and blacks showed differences in cause, neurohormonal stimulation, and pharmacological response in heart failure. This retrospective analysis suggests angiotensinconverting enzyme inhibitors are particularly effective in whites, and the H-I combination can be equally effective in blacks. Prospective trials involving large numbers of black patients are needed to further clarify their response to therapy.