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      Angiotensin II in the Failing Heart

      Kidney and Blood Pressure Research
      S. Karger AG
      Heart failure, ACE inhibitor, AT1 receptor antagonist

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          In the failing heart, the local angiotensin II concentration is increased, and the extent of cardiac angiotensin II release is related to the clinical signs of heart failure. The enzymes involved in myocardial generation of angiotensin II are the angiotensin-converting enzyme (ACE) and chymases. While myocardial angiotensin II is mainly generated by chymases in the human heart, ACE inhibitors nevertheless improve left ventricular (LV) function, attenuate LV remodelling and reduce mortality in heart failure patients. These beneficial actions of ACE inhibitors, however, relate to their beneficial effect on kinin metabolism. Angiotensin II type 1 receptor (AT1) antagonists also mediate part of their beneficial effects through increased bradykinin formation. However, in contrast to ACE inhibitors, AT1 receptor antagonists attenuate downstream signalling of angiotensin II-induced AT1 receptor activation, which increases the activity of existing proteins (e.g. NADPH oxidase) and the de novo synthesis of proteins (e.g. inducible nitric oxide synthase, tumor necrosis factor-α ) in cardiomyocytes. Given the multiple actions of AT1 receptor activation on cardiomyocyte and non-cardiomyocyte function in the presence of an increased myocardial AngII concentration, the reduction of cardiovascular mortality and rate of hospitalization following AT1 receptor blockade in heart failure patients not receiving ACE inhibitors is not surprising. Most importantly, the beneficial effects of AT1 receptor blockade are not only achieved when used as an alternative to ACE inhibition, but also when used on top of ACE inhibitors.

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          Most cited references25

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          Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial.

          Angiotensin II type 1 receptor blockers have favourable effects on haemodynamic measurements, neurohumoral activity, and left-ventricular remodelling when added to angiotensin-converting-enzyme (ACE) inhibitors in patients with chronic heart failure (CHF). We aimed to find out whether these drugs improve clinical outcome. Between March, 1999, and November, 1999, we enrolled 2548 patients with New York Heart Association functional class II-IV CHF and left-ventricular ejection fraction 40% or lower, and who were being treated with ACE inhibitors. We randomly assigned patients candesartan (n=1276, target dose 32 mg once daily) or placebo (n=1272). At baseline, 55% of patients were also treated with beta blockers and 17% with spironolactone. The primary outcome of the study was the composite of cardiovascular death or hospital admission for CHF. Analysis was done by intention to treat. The median follow-up was 41 months. 483 (38%) patients in the candesartan group and 538 (42%) in the placebo group experienced the primary outcome (unadjusted hazard ratio 0.85 [95% CI 0.75-0.96], p=0.011; covariate adjusted p=0.010). Candesartan reduced each of the components of the primary outcome significantly, as well as the total number of hospital admissions for CHF. The benefits of candesartan were similar in all predefined subgroups, including patients receiving baseline beta blocker treatment. The addition of candesartan to ACE inhibitor and other treatment leads to a further clinically important reduction in relevant cardiovascular events in patients with CHF and reduced left-ventricular ejection fraction.
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            Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme

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              Executive summary of the guidelines on the diagnosis and treatment of acute heart failure: the Task Force on Acute Heart Failure of the European Society of Cardiology.


                Author and article information

                Kidney Blood Press Res
                Kidney and Blood Pressure Research
                S. Karger AG
                March 2006
                20 March 2006
                : 28
                : 5-6
                : 349-352
                Institute of Pathophysiology, University of Duisburg-Essen, Essen, Germany
                90189 Kidney Blood Press Res 2005;28:349–352
                © 2005 S. Karger AG, Basel

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                Page count
                References: 39, Pages: 4
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/90189
                Self URI (text/html): https://www.karger.com/Article/FullText/90189
                Self URI (journal page): https://www.karger.com/SubjectArea/Nephrology
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                Cardiovascular Medicine,Nephrology
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                AT1 receptor antagonist, Heart failure, ACE inhibitor


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