Angiotensin II-induced sudden arrhythmic death and electrical remodeling

Fischer, Robert; Dechend, Ralf; Gapelyuk, Andrej; Shagdarsuren, Erdenechimeg; Gruner, Konstanze; Grüner, A.; Gratze, Petra; Qadri, Fatimunnisa; Wellner, Maren; Fiebeler, Anette; Dietz, Rainer; Luft, Friedrich C.; Müller, Dominik N.; Schirdewan, Alexander

doi:10.1152/ajpheart.01400.2006

Cited by 67 publications

(65 citation statements)

References 36 publications

(34 reference statements)

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“…These animals die suddenly between weeks 7 and 8. Recently, Fischer et al (55) reported in this high AngII model abnormal "electrical remodeling" in the left ventricle with reduced expression of the potassium channel subunit Kv4.3 and gap junction protein Cx43, as well as prolonged and inhomogeneous depolarization and repolarization. These abnormalities and the induction of ventricular tachycardia were prevented by treatment with the angiotensin receptor blocker (ARB) losartan, of interest because of recent preliminary reports of reduced cardiovascular mortality in dialysis patients on ARB (56).…”

Section: Angiotensin Ii-induced Electric Remodeling?mentioning

confidence: 90%

The Challenge of Sudden Death in Dialysis Patients

Ritz¹,

Wanner²

2008

Clinical Journal of the American Society of Nephrology

111

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A 60-yr-old patient with ESRD (82 kg/168 cm), hypertension for the previous 18 yr, and type 2 diabetes is found dead in bed by his wife at home on a Saturday morning. The patient's history is notable for having started dialysis 34 weeks previously. His last dialysis had been the previous day (on a Friday afternoon). Predialysis potassium had been 5.7 mmol/L, the dialysate K ϩ was 2.0 mmol/L, and Mg 2ϩ was 0.5 mmol/L. Autopsy was not performed.Before his morbid event, the patient had been doing well on dialysis. He had less than 6 episodes of hypotension (Ͻ100 mmHg) per month. His average predialytic weight gain was 4 kg, and, with fluctuations, his average predialysis BP was 155/65 mmHg. While continuing on gliquidone (an oral sulfonylurea hypoglycemic drug that does not accumulate in renal failure), he had no episodes of hypoglycemia, and his last glycosylated hemoglobin level was 7.2%. His medical history is of hypertension, type 2 diabetes, and left ventricular hypertrophy (LVH) with an ejection fraction of 55%. His electrocardiogram showed signs of LVH and flat T waves. He had no history of hypoglycemic episodes and no evidence of retinopathy. He reported no episodes of arrhythmia or precordial pain. A predialysis chest x-ray 2 wk before the terminal event had shown pulmonary congestion. His medications included 0.25 g/d calcitriol, calcium carbonate, 10 mg of folate, 80 mg of verapamil, and no ␤ blockers. In addition, he received varying doses of darbepoietin and iron gluconate as required. He did not receive a statin. Dr. Eberhard Ritz: This case, unfortunately, is the usual presentation of patients on dialysis who succumb to sudden death: There are few, if any, specific premonitory symptoms or signs, cardiac standstill is usually the presenting symptom, and autopsy is not performed, so more specific information on underlying cardiac pathology, if any, is not available. The lack of pathoanatomic confirmation of the underlying pathology or pathologies-as in this case-continues to remain a problem that in the future should come onto the radar screen of nephrologists.Nevertheless, this case presentation raises a number of unresolved issues and provides an occasion to discuss how the currently unsatisfactory results might be improved in the future. In this context, it is of interest to have a look at the recent 4D study.

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Section: Angiotensin Ii-induced Electric Remodeling?mentioning

confidence: 90%

The Challenge of Sudden Death in Dialysis Patients

Ritz¹,

Wanner²

2008

Clinical Journal of the American Society of Nephrology

111

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“…6,17,18 Programmed electrical stimulation was performed as reported recently 6 (please see the data supplement available at http://hyper.ahajournals.org).…”

Section: Ecg Mcg and In Vivo Electrophysiological Studiesmentioning

confidence: 99%

Dietary n-3 Polyunsaturated Fatty Acids and Direct Renin Inhibition Improve Electrical Remodeling in a Model of High Human Renin Hypertension

et al. 2008

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Abstract-We compared the effect n-3 polyunsaturated fatty acids (PUFAs) with direct renin inhibition on electrophysiological remodeling in angiotensin II-induced cardiac injury. We treated double-transgenic rats expressing the human renin and angiotensinogen genes (dTGRs) from week 4 to 7 with n-3 PUFA ethyl-esters (Omacor; 25-g/kg diet) or a direct renin inhibitor (aliskiren; 3 mg/kg per day). Sprague-Dawley rats were controls. We performed electrocardiographic, magnetocardiographic, and programmed electrical stimulation. Dietary n-3 PUFAs increased the cardiac content of eicosapentaenoic and docosahexaenoic acid. At week 7, mortality in dTGRs was 31%, whereas none of the n-3 PUFA-or aliskiren-treated dTGRs died. Systolic blood pressure was modestly reduced in n-3 PUFA-treated (180Ϯ3 mm Hg) compared with dTGRs (208Ϯ5 mm Hg). Aliskiren-treated dTGRs and SpragueDawley rats were normotensive (110Ϯ3 and 119Ϯ6 mm Hg, respectively). Both n-3 PUFA-treated and untreated dTGRs showed cardiac hypertrophy and increased atrial natriuretic peptide levels. Prolonged QRS and QT c intervals and increased T-wave dispersion in dTGRs were reduced by n-3 PUFAs or aliskiren. Both treatments reduced arrhythmia induction from 75% in dTGRs to 17% versus 0% in Sprague-Dawley rats. Macrophage infiltration and fibrosis were reduced by n-3 PUFAs and aliskiren. Connexin 43, a mediator of intermyocyte conduction, was redistributed to the lateral cell membranes in dTGRs. n-3 PUFAs and aliskiren restored normal localization to the intercalated disks. Thus, n-3 PUFAs and aliskiren improved electrical remodeling, arrhythmia induction, and connexin 43 expression, despite a 70-mm Hg difference in blood pressure and the development of cardiac hypertrophy. Key Words: angiotensin II Ⅲ renin inhibition Ⅲ n-3 PUFA Ⅲ arrhythmias Ⅲ magnetocardiography H ypertensive heart disease causes heart failure and arrhythmia propensity. Ischemia, cardiac hypertrophy, fibrosis, inflammation, and electrical remodeling all contribute to the pathogenesis. 1,2 The renin-angiotensin-aldosterone system is a primary driver, and its blockade is state-of-the-art therapy. We provided initial evidence that direct renin inhibition (DRI) in transgenic rats harboring the human renin and angiotensinogen genes (dTGRs) improves target organ damage. 3-5 Untreated dTGRs developed severe hypertension, hypertrophy, inflammation, fibrosis, and small myocardial infarctions. Ventricular arrhythmias and, consequently, sudden cardiac death contributed to the high mortality rate at the early age of 7 weeks. 6 Electrical remodeling in dTGRs included dysregulation of the I to potassium channel, Ca 2ϩ -cycling proteins, and connexin (Cx) 43 gap junctions. 6,7 n-3 polyunsaturated fatty acids (PUFAs), contained in marine fish oil, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), lead to cardioprotection and reduce sudden cardiac death. 8 The molecular mechanisms by which n-3 PUFAs exert their cardioprotective effects are not fully understood. n-3 PUFAs putatively affect membran...

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“…Some of these, such as high glucose, PKC expression/activity, and oxidative stress, are implicated in diabetic pathology (19,24,50). Importantly, gap junction remodeling, which occurs with many cardiac pathologies (6,38), may be triggered by elevated angiotensin (12,22). Thus gap junction remodeling is blocked by inhibition of angiotensin formation or by receptor blockade (7,9).…”

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confidence: 99%

Sex-dependent impairment of cardiac action potential conduction in type 1 diabetic rats

Shimoni¹,

Emmett²,

Schmidt³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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The incidence of diabetes mellitus is increasing. Cardiac dysfunction often develops, resulting in diverse arrhythmias. These arise from ion channel remodeling or from altered speed and pattern of impulse propagation. Few studies have investigated impulse propagation in the diabetic heart. We previously showed a reduced conduction reserve in the diabetic heart, with associated changes in intercellular gap junctions. The present study investigated whether these effects are sex specific. Hearts from control and streptozotocin-diabetic male and female rats were used. Optical mapping was performed with the voltage-sensitive dye di-4-ANEPPS, using Langendorff-perfused hearts. Isolated ventricular cells and tissue sections were used for immunofluorescent labeling of the gap junction protein connexin43 (Cx43). The gap junction uncoupler heptanol (0.75 mM) or elevated K+ (9 mM, to reduce cell excitability) produced significantly greater slowing of propagation in diabetic males than females. In ovariectomized diabetic females, 9 mM K+ slowed conduction significantly more than in nonovariectomized females. The subcellular redistribution (lateralization) of the gap junction protein Cx43 was smaller in diabetic females. Pretreatment of diabetic males with the angiotensin-converting enzyme inhibitor quinapril reduced Cx43 lateralization and the effects of 9 mM K+ on propagation. In conclusion, the slowing of cardiac impulse propagation in type 1 diabetes is smaller in female rats, partly due to the presence of female sex hormones. This difference is (partly) mediated by sex differences in activation of the cardiac renin-angiotensin system.

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Angiotensin II-induced sudden arrhythmic death and electrical remodeling

Cited by 67 publications

References 36 publications

The Challenge of Sudden Death in Dialysis Patients

The Challenge of Sudden Death in Dialysis Patients

Dietary n-3 Polyunsaturated Fatty Acids and Direct Renin Inhibition Improve Electrical Remodeling in a Model of High Human Renin Hypertension

Sex-dependent impairment of cardiac action potential conduction in type 1 diabetic rats

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