renin-angiotensin system | Definition & Facts | santoriniinfo.info
Dec 1, Components of the renin–angiotensin–aldosterone system (RAAS) and a The relationship of PRA with fibrinogen and PAI-1 remained .. organs and prevention of major cardiovascular events are primary goals of treatment. May 10, The renin-angiotensin-aldosterone system is one of the most complex Angiotensinogen's purpose is to serve as a precursor to angiotensin I. Sep 22, figure 1 | The interacting relationship between body sodium and the circulating renin–angiotensin system to . high aldosterone levels but very low plasma renin levels.1,2 Thus, in more .. The purpose of this figure is to show.
One reason is the danger of hyperkalemia secondary to mineralocorticoid [ 52 ]. More recently the results of the ADHERE Acute Decompensated Heart Failure Registry indicated the need for better treatment for acute cardiac decompensation [ 53 ] shows that genomic dosages of mineralocorticoid antagonists are in need of study in patients who have decompensated HF and are receiving a lowpotassium diet and no potassium supplements.
The diuretic resistance of loop diuretics common in these patients may be reversed with mineralocorticoid antagonists, and the resultant increased urinary potassium losses may also protect against any clinically relevant hyperkalemia in patients who have cardiac failure and receive the combination of ACEI and spironolactone [ 45 ].
Aldosterone in CVD and hypertension Aldo plays a pathological role in CVD and kidney disease in part due to its mitogenic effects on a number of cell types in the systemic vasculature, heart and kidney [ 54 ]. Other mechanism involve in Aldo CV injury include inflammation, oxidative stress, activation and enhancement of AII and accelerated fibrosis [ 46 ].
After binding to the MCR, Aldo is translocated into the nucleus, in which the complex dissociates and binds to regulatory regions of multiple genes that stimulate production of proteins involved in both sodium and potassium transport as well as inflammation and oxidative stress. There is evidence of a nongenomic effect of Aldo to injure the endothelium, which could contribute to elevated BP and be prevented by a mineralocorticoid antagonist [ 45 ].
The role of Aldo in hypertension was shown in three-drug—resistant hypertension. Interestingly this trial also showed that decrements in BP were the same in three-drug—resistant hypertension in patients with and without primary hyperaldosteronism. Three-drug—resistant hypertension may also be associated, particularly in obese patients, with obstructive sleep apnea, although the relation of these finding with Aldo have not been evaluated.
Experimental models of CKD have demonstrated a key role for Aldo-mediated glomerular and tubular injury and inflammation. Both tubulointerstitial damage and glomerular injury, particularly of the podocytes, occurs secondary to this nongenomic effect of Aldo [ 45 ]. Blockade of the MCR using drugs like spironolactone and eplerenone attenuate or abrogate all these effects [ 57 ].
An interesting finding is that some of the beneficial effects of Aldo blockade are believed to be, in part, by improvement in endothelial dysfunction [ 57 ]. Also a correlation between proteinuria and plasma Aldo has been shown to occur in patients with CKD [ 58 ]. Studies in type 2 diabetes also have demonstrated that spironolactone decreases systolic and diastolic BP as well as urinary protein and albumin excretion as compared with placebo [ 60 ].
The mechanism by which Aldo blockade reduces proteinuria is incompletely understood. Blockade of the MCR is accompanied by lowering of systemic BP that in turn is well known to lower proteinuria in patients with CKD and uncontrolled hypertension. However there are some evidence that in patients with diabetic nephropathy that the antiproteinuric effect of mineralocorticoid receptor blockade MRB is at least in part mediated by a direct effect on the glomerular basement membrane and is not dependent solely on reduction in systemic BP, glomerular filtration or dietary factors [ 57 ].
What is less well established is the effect of spironolactone on slowing the loss of GFR. However, a recent study shows that the monthly rate of decrease in estimated GFR at one year was significantly less in the spironolactone-treated group than in the placebo group [ 58 ]. ACE 2 and A Many of these components have opposing functions to accommodate a rapid but balanced response to specific triggers. However, recent studies have also demonstrated the importance of ACE2 and A in maintaining the balance of the RAAS, in both health and disease [ 61 ].
ACE2 is a type 1 integral membrane glycoprotein that is found in most tissues, with the highest expression observed in the kidney, the endothelium and in the heart [ 62 ]. A is an heptapeptide and is produced through hydrolysis of AII. It has been describe two biochemical pathways that participate on its formation: Recently a third pathway leading to the ultimate generation of A may result from the discovery of an extended form of AI, the dodecapeptide angiotensin 1—12 [ 63 ].
A has a receptor, Mas, a G-protein coupled receptor originally linked to modulation of growth regulating pathways involved in oncogenic effects [ 63 ].
Additional evidence suggests that a reduction in the expression and activity of this vasodepressor component may be a critical factor in mediating the progression of CVD [ 63 ]. In summary the discovery that A opposes the pressor, proliferative, profibrotic, and prothrombotic actions mediated by AII has contributed to the realization that the RAAS is composed of two opposing arms: Its activation in the heart leads to both accelerated atherosclerosis and direct cardiac injury that result from the activation of a complex range of pathogenic pathways.
Also several studies showed that actions leading to RAAS blockade were able to attenuate or prevent cardiac damage, independent of BP lowering. The expression of ACE2 in the failing human heart is generally increased, consistent with the finding of elevated levels of A 1—7 in the same setting [ 66 ]. Recently, experimental studies in mice have shown beneficial cardiac effects with recombinant ACE2 rAC2 [ 67 ]. So it seems that increasing ACE2 activity may provide a new therapeutic target in states of AII overactivity by enhancing its degradation.
As previously said, activation of the RAAS constitutes a key mediator of hypertension. The antihypertensive efficacy of those agents that blocks the system is mediated not only by their ability to reduce AII or its signaling, but also by the ability of both to increase circulating levels of A [ 61 ].
ACE2, which metabolizes AII and generates A 1- 7influences not only the development of hypertension, but also potentially the response to its treatment. A number of studies have demonstrated the altered regulation of ACE2 in various experimental models of hypertension. Moreover, interventions to augment the expression or activity of ACE2 have been shown to significantly reduce BP levels [ 67 ]. In experimental models A has been related to the pathogenesis of human essential hypertension based on its counterregulatory actions that causes an antihypertensive effect [ 68 ].
Clinical studies supporting these favorable actions of A show an increased excretion of A in the urine of essential hypertensive patients whose BP was controlled by a 6-month treatment with captopril [ 69 ].
Additional studies showed that administration of irbesartan was associated with increases in plasma A concentrations [ 70 ]. In summary all of these data suggest that is the balance of ACE and ACE2 in the heart, and their action to counterbalance AI and A 1- 7 that appears to be the most important driving factor in progressive cardiac disease and hypertensive disease.
The research done to-date continues to support the hypothesis that a decrease in the expression or activity of A renders the cardiovascular system more susceptible to the pathological actions of AII.
ACE2 is present in high levels in the adult kidney, predominantly expressed in the proximal tubule at the luminal brush border [ 61 ]. Experimental evidence has demonstrated several actions of ACE2 and A in the regulation of nephron function [ 72 ].
Also recent studies show that altered ACE2 expression or activity contributes to the progression of renal disease and diabetic nephropathy [ 61 ].
In most forms of CKD, including diabetes, ACE2 expression levels are reduced in tubules, but increased in glomeruli [ 73 ]. It is possible that this differential expression pattern of glomerular and tubular ACE2 is an important determinant for progressive renal disease. However there are some confounding effects of ACE2 related with some of the actions of A on the kidney.
Although A is generally regarded as an antagonist of AII mediated injury and dysfunction [ 63 ] it has been recently observed that A is able to induce epithelial-tomesenchymal transition of tubular cells, which potentially contributes to the renal accumulation of matrix proteins that is associated with progressive renal disease [ 61 ]. These data provide additional support for an important interaction among ACE2 and A in multiple disease states. The resultant peptide fragments are found in the circulation, and have functions that might be distinct from those of AII [ 74 ].
There is a relatively new addition to the family of RAAS effectors, A [ 77 ] that is produced directly from angiotensinogen by a non-renin enzyme. It contains the 12 amino acids from the N-terminus of angiotensinogen and can act as a precursor for the generation of AII by chymase. The biological significance of these novel peptides is now being investigated in several laboratories.
The finding that AII and Aldo are proinflammatory, profibrotic, and can cause oxidative injury, has led to the development of several agents that inhibit the RAAS. The pharmacological inhibition of the RAAS can be obtained through three different basic mechanisms: Thus drugs acting on the RAAS include: However, the various methods used to inhibit the RAAS differ in terms of their biochemical effects [ 78 ].
Although single-site RAAS inhibitors allow mainly for inhibition of both the circulating and tissue RAAS, depending on their primary target and the distribution of the drug, alternative mechanisms may be involved in their overall pharmacodynamic effect. Non-ACE pathways may be activated in some pathologic situations. Little is known about the physiologic consequences of activating these receptors but if their activation should prove to be deleterious, an issue that remains seriously debated, then renin inhibitors would have clinical advantages over alternative RAAS inhibitors [ 8081 ].
AcSDKP has been shown to have an antiproliferative and antifibrotic effect on the heart and the kidney in vitro and in vivo [ 79 ]. The beneficial effects of BP-lowering treatments on the risks of major CV events are well established [ 83 ]. The interruption of the RAAS with the above mentioned agents or its combination has been shown to be an effective strategy for lowering BP. However the organprotecting effects of RAAS inhibitors are thought to be independent of their effects on BP and physicians should keep in mind that the RAAS has a critically important role in maintaining homeostasis of body fluid volume and BP.
Several trials with drugs operating on ACE and on AII receptors have shown their benefits beyond BP control, such as preventing progression of renal dysfunction [ 84 ] and decreasing CVD mortality and morbidity [ 8586 ].
Recently, a systematic review of the literature that directly compare the effects of taking ACEI versus ARB on patient-level CV and kidney outcomes in a large number of albuminuric patients showed that the two classes of RAAS inhibitors were comparable with respect to all CV and kidney outcomes evaluated [ 84 ]. These findings are in keeping with those of a previous meta-analysis, which reported that the magnitudes of reduction in proteinuria following ARBs and ACEIs therapy are similar [ 89 ].
Although monotherapy with ACEIs and ARBs resulted in significant improvements in both CV and kidney end points, these did not translate into a consistent reduction in all-cause mortality. The ACEIs are a heterogeneous group, both in terms of chemical structure and pharmacokinetics. They are unified only in their ability to associate competitively with the active binding site of ACE. They are categorized into three subgroups according to their mode of metabolism: However, ACEIs also differ within these groups in their bioavailability, protein binding, lipid solubility, affinity to the ACE binding site, duration of onset, half-life and potency [ 13 ].
While the onset and duration of action are important considerations in terms of dosing, there is no evidence to suggest that the other differing pharmacokinetic properties are of clinical significance. Perhaps the best evidence in support of this comes from experience with captopril. Despite being the least potent of the class and weakly lipophilic, when used at an appropriate dose it has been shown in the SAVE and ISIS-4 trials to be similar to other ACEIs in reducing mortality and morbidity in the HF and postinfarction settings [ 9293 ].
ACEIs proved to be highly successful in the treatment of hypertension and related target-organ damage, including left ventricular hypertrophy, HF, and postmyocardial infarction left-ventricular remodeling, renal insufficiency, and diabetes with proteinuria. ACEIs differ in their ability to penetrate and bind tissue sites for prolonged periods [ 13 ]. There are a plethora of reported adverse reactions ascribed to ACEIs.
Those most clinically important are hypotension, renal impairment, hyperkalaemia, cough and angioedema. ACEI induced hypotension is accentuated by concomitant hypovolemia, unstable cardiac failure or hyponatraemia. Patients with severe left ventricular outflow tract obstruction may become profoundly hypotensive following ACEI administration, and therefore severe aortic stenosis is an absolute contraindication. Significant renal impairment occurs predominantly in patients with renovascular disease and particularly in those with severe bilateral renal artery stenosis.
This is due to a combination of the reduction in systemic BP and the inhibition of AII-mediated renal efferent arteriolar vasoconstriction. ACEIs can also affect the renal function of patients with significant renal parenchymal disease, although these drugs play an important role in the treatment of patients with impaired renal function [ 96 ]. Pre-existing renal impairment also increases the risk of hyperkalaemia.
Cough is also a common reason for ACEI intolerance. By contrast, angioedema is potentially fatal but rare and not always life threatening, with a reported incidence of approximately 0.
ACEIs are teratogenic and therefore contraindicated in pregnancy. This is a major issue if their use is contemplated in young women. ACEIs have several important interactions with other drugs. Concomitant potassium supplements and potassium-sparing diuretics will also potentiate the risk of hyperkalemia [ 90 ].
ACE inhibition is more effective in patients with high levels of renin activity, and it follows that hypotension is more likely in patients with pre-existing hypotension, hypovolemia or hyponatremia. Thus, diuretics may intensify the BP lowering effects of ACEIs, as may the concomitant use of any negative inotropic agents eg beta-blockers, calcium- channel blockers. In patients with severe impairment of left ventricular function the use of ACEIs may be precluded. Conversely, this interaction is helpful in the setting of hypertension.
They do not interact with ATR2s. The AII generated may interact with ATR2s, an effect that may result in vasodilatation and further BP reduction and, according to some recent experimental evidence, may result in inhibition of angiotensin and revascularization [ 38 ]. The ARBs are highly effective and well-tolerated antihypertensive medications, and recent clinical trials have shown that these agents have renoprotective effects beyond lowering BP [ 98 ].
There are currently 7 ARBs available: Pharmacologic differences exist for the various ARBs; however, differences in antihypertensive potency and duration of action of the ARBs have been inconsistently reported [ ]. In fact there is no data that clearly and convincingly separate one ARBs from the other based on differing mechanisms of action and pharmacologic differences such as bioavailability, protein binding, and half-life [ 99 ].
Bioavailability has been touted as a way to distinguish ARBs from another. Three of the ARBs are administered in a prodrug form-losartan, candesartan cilexitil, and olmesartan medoxomil-although, technically speaking, losartan is an active compound, albeit one ultimately converted to its more potent metabolite.
Although there is a considerable degree of variance in bioavailability between individual ARBs, this pharmacologic parameter has a limited effect on drug response and cannot be viewed in isolation from the other core pharmacologic features of an ARB [ ]. In general, none of the ARBs bind to partitions in red blood cells in a meaningful fashion. Furthermore, the extent of protein binding for the ARBs remains constant over a wide concentration range.
Heavily protein-bound drugs generally have a small volume of distribution; however, protein binding is not always an accurate predictor of volume of distribution. While telmisartan and losartan have similar protein binding, telmisartan has a lesser affinity for the albumin receptor and therein a much larger volume of distribution [ 99 ]. The discrepancy between the pharmacokinetic and pharmacodynamic half-life of a compound comes from the fact that a component of drug action derives from extravascular effects.
Because of the inability to sample at these extravascular sites of action, the more meaningful tissue-based half-life cannot be determined. This is particularly the case for the ARBs, since AT1Rs are found in multiple extravascular locations and blocking these receptors, may, in an as-of-yet undefined fashion, influence the manner in which BP is reduced [ ].
With the above in mind, the pharmacokinetic half-life of an ARB will roughly approximate its duration of effect as long as the plasma concentration of an ARB remains above the threshold for a BP-lowering effect.
Several of the ARBs, such as candesartan, olmesartan, telmisartan, and irbesartan, are considered once-daily compounds in pharmacokinetic terms. The true impact of pharmacologic half-life for these compounds probably lies more so in the fact that the drug is available for a longer period and thereby binds to additional AT1Rs as they are formed during the latter portion of a dosing interval.
Differentiation of one ARB from the other requires that drugs be studied in the same patient types and therein variable responses sought. Without a homogeneous population, heterogeneity weights results toward more non-responders, which is both a phenotypically and genotypically difficult state to characterize.
ARBs are fairly equivalent at their low-end and high-end doses, with the probable exception of losartan.
The Renin Angiotensin Aldosterone Reflex
If a patient is a responder to an ARB, it is evident even at low-end doses. Thus, in those studies where BP is not the most important determinant of response, the results are then more so a matter of the specific dosing with a particular compound. A pertinent example of this is found in the Valsartan Heart Failure Trial Val-HeFT wherein valsartan was administered at a maximum dose of mg twice daily [ ]. The primary end point was all-cause mortality and the secondary end point was sudden death or resuscitated arrest.
The study did not have a superior outcome with losartan; however, losartan was administered only once daily at a low-end dose and this was believed by many to be the basis for the comparable response between captopril and losartan [ ].
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These findings could be interpreted to represent an intraclass difference when in point-of-fact they represent inadequate dosing. This is another of the vagaries in attempting to unravel the issue of class effect for individual ARBs [ ].
Recently, another possible beneficial effect of telmisartan on metabolic syndrome has been described. In fact, this ARB can function as a partial agonist of peroxisome proliferator-activated receptor [ ]. The clinical significance of these differences among members of the class remains to be determined in outcome trials. ARBs can thus be characterized as having a wide therapeutic window, with virtually no dose-dependent side effects.
This finding, taken together with some data of improved outcomes at higher doses, suggests higher doses might provide better target organ protection. However, in those studies exploring the efficacy of such combinations in order to control BP in patients with type 2 diabetes mellitus did not showed any increased risk of mortality [ ]. Renoprotection with both drugs have invariably shown that their renoprotective benefit is mainly explained by their specific antiptoteinuric effects.
This is consistent with the view that proteins, once leaked through the glomerular barrier, act as mediators of ongoing renal fibrosis [ ]. Thus in patients with renal disease reducing albuminuria remain an important strategy for renal and cardiovascular protection.
The experimental demonstration that the blockade of AII with an ACEI slowed the progressive loss of renal in a number of animal models or renal diseases, including diabetic nephropathy, offered the opportunity, for the first time, to devise a treatment strategy that was not limited to passively accompany patients to their destiny of dialysis, but was aimed to preserve renal function as long as possible . Based in these circumstances and several experimental and clinical studies emerged the concept of renoprotection [ ].
The development of a new class of the drugs, the ARBs has offered another opportunity to further improve the renoprotection. In fact the near complete abolition of AII activity is instrumental to achieve full renal protection. Thus the combination of the two drugs, an ACEI and an ARB, in an experimental model of chronic nephropathies was associated with greater reduction of proteinuria and a trend toward less renal injury than with each drug alone [ ].
Until now, it has considered as the main goal of current treatments the arrest of renal disease progression, however, the kidney has a great potential of regeneration after injury. Experimental evidence is accumulating that there is potential for regression of renal scarring, as shown in a paper by Fogo, in which the mechanisms of regeneration are reviewed [ ].
Of note, the potential antifibrotic role of drugs that block the RAAS system is underlined [ ]. Despite many uncertainties and as yet unknown factors, regression of human kidney disease now represents a realistic potential clinical target.
A relevant body of evidence, based in experimental and clinical studies, indicates that, by mechanism yet to be define, the glomerular capillary network can sometimes undergo a process of both structural and functional regeneration [ ]. In relation to the regression phenomena in chronic nephropathies, there are three main issues open for investigation. First, it is still a matter of controversy whether regression can be achieved in a consistent percentage of patients and to what extent .
Second, there are some disparities between the extent of the observed regression of structural changes and its translation into effective improvement of kidney function. At present, we know that controlling proteinuria seems to be a relevant factor for the progression of the disease [ ]. The third refers to that the regression of renal lesions can be achieved in all progressive forms of glomerulopathies, or will only some types of renal diseases respond [ ]. Recent clinical data showed that for patients at low renal risk and with low levels of albuminuria, RAAS inhibition might not offer any renal benefit [ ].
In these patients agents that blocks RAAS should be used sparingly, doses should be titrated to individual needs and kidney function should be monitored closely. Although RAAS blockade is thought to have major nephroprotective properties in individuals with diabetes, attention should be devoted to the identification of patient subgroups that can profit most from this treatment regimen.
In addition, results from the RASS study, performed in type 1 diabetes mellitus patient with normal BP and normoalbuminuria, strongly suggest that trials of RAAS blockade in patients with diabetes and a low CV burden require a much longer follow-up period than is usually assumed [ ]. Such trials of longer duration are needed to establish whether such a treatment regimen offers clinical benefit in the primary prevention of both microvascular and CV complications, which remain the major cause of morbidity and mortality in patients with diabetes [ ].
This suggests that treatments suppressing the RAAS might exert an additional specific cardioprotective effect compared to non-RAAS inhibiting antihypertensive medications. In the general population as well as in specific high-risk patient subgroups ACEIs are the antihypertensive agents with the best risk-benefit profile. They also improve survival of patients with HF or left ventricular dysfunction, previous myocardial infarction, stroke, or transient ischemic attack or with peripheral vascular disease and diabetes [ 9294].
Studies have shown the efficacy of ACEIs in all symptomatic classes of systolic HF patients including those patients with some degree of renal dysfunction. Thus, a meta-analysis of five randomized trials of ACEI therapy in patients with HF showed that although the proportion of patients who developed renal dysfunction was higher in the ACEI groups than in the placebo groups, drug discontinuation was required in only a small percentage of patients, and renal function returned to baseline in most patients even without dose adjustment [ 92 ].
A retrospective analysis of the studies of left ventricular dysfunction SOLVD has shown that the use of ACEIs was associated with a reduced risk of mortality, even at moderately and severely depressed levels of GFR, and did not have an adverse impact on kidney function [ ]. Therefore, in patients with chronic HF CHFmild-to-moderate renal insufficiency should not be viewed as a contraindication to ACEI therapy, and a mild and nonprogressive worsening of renal function during initiation of therapy should not be considered an indication to discontinue treatment, as the drug may offer the dual benefit of reducing disease progression in both the heart and the kidney [ ].
In patients with moderate or severe renal insufficiency, therapy with low doses of ACEIs should be initiated and the dose should be increased gradually with careful monitoring of renal function and serum electrolytes. First, ACEIs should be discontinued, and the patients should be evaluated for conditions causing renal hypoperfusion in which the use of ACEIs may result in acute renal failure, such as excessive depletion of circulating volume due to intensive diuretic treatment, concurrent administration of vasoconstrictor agents eg, nonsteroidal anti-inflammatory drugs- NSAIDs and severe bilateral renal artery stenosis.
Unless renal vascular disease is present, therapy with an ACEI can be reinstituted after correction of the underlying cause of reduced renal perfusion [ ]. Plasma aldosterone levels were directly correlated with fibrinogen, D-dimer, and PAI-1, whereas plasma angiotensin-converting enzyme was not related with any of the coagulation parameters.
Both fibrinogen and PAI-1 were independent predictors of the presence of organ damage and their inclusion in a multivariate model eliminated PRA and aldosterone as independent predictors.
Conclusions A strong and independent association exists between renin, aldosterone, and markers of a prothrombotic state in essential hypertension. This relationship might contribute to the development of hypertensive organ damage. Although the incidence of cardiovascular events is directly related with the level of blood pressure, 1 the propensity of hypertensive patients to develop organ damage is under the influence of coexisting risk factors such as diabetes, dyslipidemia, smoking, and obesity.
In addition to these classic risk factors, other systems contribute to the atherosclerotic process and may affect the impact of hypertension on the occurrence of cardiovascular events. Landmark studies 23 demonstrated that an activated renin—angiotensin—aldosterone system RAAS is associated with an increased risk of coronary and cerebrovascular events independent of blood pressure levels and substantial evidence has subsequently linked pharmacological inhibition of the RAAS with effective cardiovascular 4 and renal 5 protection in hypertensive patients.
In addition to its pressor effects, the RAAS has been associated with a variety of nonhemodynamic actions that might contribute to the progression of cardiovascular and renal pathology. In hypertension, the link between the RAAS and the coagulation—fibrinolytic system is indirectly supported by the findings of a series of elegant studies conducted with RAAS blockers.
Stroke, High Blood Pressure and The Renin–Angiotensin–Aldosterone System – New Developments
To test this hypothesis, we have measured components of the RAAS and parameters that directly assess the activation of coagulation and fibrinolysis in a large group of hypertensive patients in whom the extent of organ damage has been characterized. Overall, patients age: Blood pressure was measured using a mercury sphygmomanometer according to current guidelines, and diagnosis of hypertension was established by standard criteria. History and medical records were used to estimate duration of hypertensive disease this ranged from 3 months to 25 years.
None of the patients included in the study had received drug-eluting stents for coronary heart disease in the past 2 years. Secondary causes of hypertension were excluded on the basis of extensive laboratory testing. Hypertension-related organ damage was assessed in all patients by history, clinical examination, and laboratory tests including measurements of h creatinine clearance, h proteinuria, electrocardiography, echocardiography, and ultrasound examination of aorta, carotid, iliac, and femoral arteries as performed in previous studies to which readers are referred for further details.
The retrospective diagnosis of myocardial infarction was confirmed by documented history, electrocardiographic changes, and greater than twofold elevation of the serum creatinine kinase with positive muscle—brain fraction. The neurological diagnosis of transient ischemic attack and stroke was confirmed by documented history, clinical signs, and computerized cerebral axial tomography.
The assessment of the cardiovascular status was performed without prior knowledge of patients' biochemical parameters. Depending upon the type of drugs, withdrawal was longer up to 5 weeks for RAAS blockers and statins.