Mechanisms of Angiotensin II-Dependent Progression to Heart Failure

2008 ◽  
pp. 58-72 ◽  
Author(s):  
Mona Nemer ◽  
Nassim Dali-Youcef ◽  
Hao Wang ◽  
Anne Aries ◽  
Pierre Paradis
Keyword(s):  
Heart Failure ◽  
Angiotensin Ii

Treatment of heart failure

2000 ◽  
Vol 57 (5) ◽  
pp. 313-320
Author(s):  
Just
Keyword(s):  
Heart Failure ◽  
Angiotensin Ii ◽  
Beta Blocker ◽  
Medikamentöse Therapie ◽  
Antiarrhythmische Therapie

Die Therapie der Herzinsuffizienz umfasst drei Schritte: 1. Elimination der auslösenden Ursache bzw. Behandlung der Grunderkrankung 2. Behandlung der Herzinsuffizienz selbst (dabei soll hier die medikamentöse Therapie besprochen werden) 3. Prophylaxe von Komplikationen. Für die Therapie der Herzinsuffizienz werden Pharmaka aus vier Gruppen meistens in Kombination eingesetzt: 1. Diuretika 2. Vasodilatantien 3. Neurohumorale Inhibitoren 4. Inotrop wirkende Pharmaka Diuretika verbessern die Befindlichkeit und Leistungsfähigkeit, wahrscheinlich auch die Lebenserwartung. Sie sind in der akuten und der chronischen Herzinsuffizienz Medikamente der ersten Wahl. In der Langzeittherapie ist Rückwirkungen auf die Niere und den Kaliumspiegel Rechnung zu tragen. Der Kaliumsparer und Aldosteronantagonist Spironolacton besitzt möglicherweise einen besonderen Stellenwert: Er vermag die myokardiale Bindegewebsproliferation zu hemmen. Vasodilatantien entlasten das Herz akut und chronisch. Gesichert ist diese Wirkung akut für alle gebräuchlichen Substanzen; chronisch für die Kombination von Nitraten mit Hydralazin gemessen an der Verbesserung der Lebenserwartung. Besonders wirksam sind Angiotensin converting Enzym Hemmer (ACE-I), welche Vasodilatation mit neurohumoraler Inhibition verbinden. Hier werden Symptomatik, Leistungsfähigkeit und Lebenserwartung verbessert. Angiotensin II-Rezeptor-Antagonisten sind ähnlich wirksam. Sie können bei Nebenwirkungen der ACE-I austauschbar eingesetzt werden. Beta-Rezeptorenblocker haben einen hohen Stellenwert. Sie sollten, wenn immer verträglich, im Schweregrad II, III und IV (Vorsicht!) in ganz langsam einschleichender Dosierung gegeben werden. Der Wirkungsmechanismus ist nicht ganz geklärt. Wahrscheinlich spielt die Senkung der Herzfrequenz eine entscheidende Rolle. Inotrop wirkende Pharmaka werden kaum verwendet, nur in der akuten Herzinsuffizienz und im kardiogenen Schock. Digitalisglykoside sind wirksam. Sie verbessern die Symptomatik und die Leistungsfähigkeit und reduzieren die Zahl der Dekompensationen im Verlauf. Eine Wirkung auf die Letalität ist nicht gesichert, wohl im Zusammenhang mit der engen therapeutischen Breite dieser Pharmaka. Zur Prävention von Komplikationen wird oft eine antiarrhythmische Therapie notwendig. Diese stützt sich im Wesentlichen auf Amiodaron bzw. die Beta-Blocker. Ferner ist bei Herzinsuffizienz NYHA III und IV, wann immer möglich, eine prophylaktische Antikoagulierung erforderlich. Die Fortschritte im Verständnis der Pathophysiologie und damit der Therapie sind außerordentlich. Neuentwicklungen sind besonders auf dem Gebiet der Zytokine und der Gentherapie zu erkennen.

scholarly journals Oxidative Stress as A Mechanism for Functional Alterations in Cardiac Hypertrophy and Heart Failure

Antioxidants ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 931
Author(s):  
Anureet K. Shah ◽  
Sukhwinder K. Bhullar ◽  
Vijayan Elimban ◽  
Naranjan S. Dhalla
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Cardiac Remodeling ◽  
Cardiac Dysfunction ◽  
Critical Role ◽  
Pressure Overload ◽  
Hypertrophied Heart ◽  
Vasoactive Hormones

Although heart failure due to a wide variety of pathological stimuli including myocardial infarction, pressure overload and volume overload is associated with cardiac hypertrophy, the exact reasons for the transition of cardiac hypertrophy to heart failure are not well defined. Since circulating levels of several vasoactive hormones including catecholamines, angiotensin II, and endothelins are elevated under pathological conditions, it has been suggested that these vasoactive hormones may be involved in the development of both cardiac hypertrophy and heart failure. At initial stages of pathological stimuli, these hormones induce an increase in ventricular wall tension by acting through their respective receptor-mediated signal transduction systems and result in the development of cardiac hypertrophy. Some oxyradicals formed at initial stages are also involved in the redox-dependent activation of the hypertrophic process but these are rapidly removed by increased content of antioxidants in hypertrophied heart. In fact, cardiac hypertrophy is considered to be an adaptive process as it exhibits either normal or augmented cardiac function for maintaining cardiovascular homeostasis. However, exposure of a hypertrophied heart to elevated levels of circulating hormones due to pathological stimuli over a prolonged period results in cardiac dysfunction and development of heart failure involving a complex set of mechanisms. It has been demonstrated that different cardiovascular abnormalities such as functional hypoxia, metabolic derangements, uncoupling of mitochondrial electron transport, and inflammation produce oxidative stress in the hypertrophied failing hearts. In addition, oxidation of catecholamines by monoamine oxidase as well as NADPH oxidase activation by angiotensin II and endothelin promote the generation of oxidative stress during the prolonged period by these pathological stimuli. It is noteworthy that oxidative stress is known to activate metallomatrix proteases and degrade the extracellular matrix proteins for the induction of cardiac remodeling and heart dysfunction. Furthermore, oxidative stress has been shown to induce subcellular remodeling and Ca2+-handling abnormalities as well as loss of cardiomyocytes due to the development of apoptosis, necrosis, and fibrosis. These observations support the view that a low amount of oxyradical formation for a brief period may activate redox-sensitive mechanisms, which are associated with the development of cardiac hypertrophy. On the other hand, high levels of oxyradicals over a prolonged period may induce oxidative stress and cause Ca2+-handling defects as well as protease activation and thus play a critical role in the development of adverse cardiac remodeling and cardiac dysfunction as well as progression of heart failure.

Role of angiotensin-signalling in anthracycline-induced cardiotoxicity

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
S Findlay ◽  
J.H Gill ◽  
R Plummer ◽  
C.J Plummer
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Angiotensin Ii ◽  
Late Onset ◽  
Left Ventricular Systolic Dysfunction ◽  
Left Ventricular ◽  
Cardiomyocyte Hypertrophy ◽  
Funding Source ◽  
Study Results

Abstract   Anthracycline chemotherapy remains a key component of cancer treatment regimens in both paediatric and adult patients. A significant issue with their use is the development of anthracycline-induced cardiotoxicity (AIC), with subclinical AIC and clinical heart failure observed in 13.8% and 3.1% of patients, respectively. The major clinical complication of AIC is the development of late-onset cardiotoxicity, occurring several years after drug administration, presenting as life-threatening heart failure (HF). Determining the relationship between subclinical AIC and late-onset HF, strategies for mitigation of AIC, and impacts upon the cancer survivor population remains a complex challenge. Administration of drugs targeting the angiotensin system, specifically angiotensin converting enzyme inhibitors (ACEi), have been reported to reduce AIC in the clinic. Whilst the therapeutic effect of ACEi in management of left ventricular systolic dysfunction and consequent HF is principally through optimisation of cardiac haemodynamics, the mechanism involved with mitigation of late-onset AIC several years after anthracycline exposure are currently unknown. Using a variety of human cardiomyocyte in vitro models we have previously demonstrated induction of cardiomyocyte hypertrophy by angiotensin II and anthracyclines. Importantly, selective blockade of the angiotensin II receptor 1 (ATR1) on cardiomyocytes mitigated the anthracycline-induced hypertrophic response, implicating synergism between AIC and angiotensin signalling in cardiomyocytes. Adult human ventricular cardiac myocyte AC10 cell-line were treated in vitro with a range of clinically relevant doxorubicin doses for clinically appropriate durations, with AT1 receptor gene expression evaluated using semi-quantitative PCR. Our results confirm a positive correlation between clinically-relevant concentration of doxorubicin and induction of genetic expression of ATR1 in AC10 cells, with up to 200% increases in ATR1 expression observed. Maximal doxorubicin-induced gene expression being observed at 8 and 24-hours, respectively. These preliminary results agreeing with clinical exposure parameters for this drug with protein expression studies being optimised to support these gene expression study results. Our preliminary studies also imply patients developing AIC carry a deleted polymorphism within intron 16 of the ACE gene and increased systemic levels of the ACE product angiotensin II, both with a known association to hypertrophic cardiomyopathy. Taken together, these data support our mechanistic hypothesis that a relationship exists between AIC and modulation of the angiotensin signalling pathway in cardiomyocytes, involving structural cellular changes and asymptomatic cardiac hypertrophy. An elevation in angiotensin II levels, potentially through polymorphisms in ACE, could thereby exacerbate anthracycline-induced hypertrophy and promote the development of late-onset anthracycline-induced HF. Funding Acknowledgement Type of funding source: Private grant(s) and/or Sponsorship. Main funding source(s): Cancer Research UK funded PhD

Angiotensin II Receptor Type 1 mRNA is Upregulated in Atria of Patients with End-stage Heart Failure

1997 ◽  
Vol 29 (8) ◽  
pp. 2299-2304 ◽  
Author(s):  
Raffi R Kaprielian ◽  
Emmanuel Dupont ◽  
Sassan Hafizi ◽  
Philip A Poole-Wilson ◽  
Asghar Khaghani ◽  
...  
Keyword(s):  
Heart Failure ◽  
Angiotensin Ii ◽  
Receptor Type ◽  
Angiotensin Ii Receptor ◽  
End Stage Heart Failure ◽  
End Stage

Abstract 180: Synergistic Salutary Effects of HMG-CoA Reductase Inhibitor and Angiotensin II Receptor Blocker on Load-induced Heart Failure

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Yasuhiro Maejima ◽  
Mitsuaki Isobe
Keyword(s):  
Heart Failure ◽  
Angiotensin Ii ◽  
Reductase Inhibitor ◽  
Neonatal Rat ◽  
Receptor Blocker ◽  
Angiotensin Ii Receptor Blocker ◽  
Angiotensin Ii Receptor ◽  
Hmg Coa Reductase ◽  
Hmg Coa Reductase Inhibitor ◽  
Coa Reductase

We have shown previously that combined HMG-CoA reductase inhibitor (statin) and angiotensin II receptor blocker (ARB) therapy significantly improves both symptoms and left ventricular (LV) function over time in patients with heart failure (HF) by a clinical study [ HF-COSTAR Trial]. We elucidated the mechanisms of combination therapy with the ARB (losartan, LOS) and long-acting and statin (simvastatin, SIM) for the treatment of load-induced heart failure. Salt-loaded Dahl salt-sensitive (DS) rats were treated with vehicle, LOS (5mg/kg/day), SIM (2mg/kg/day) and LOS + SIM for 16 weeks. LOS and SIM in combination improved LV dysfunction (ΔLV fractional shortening; LOS = 60%, SIM = 42%, LOS + SIM = 24%, p <0.05), limited LV hypertrophy (ΔLV septal thickness; LOS = −21%, SIM = −18%, LOS + SIM = −13%, p <0.05) and reduced cardiac fibrosis (ΔLV collagen density; LOS = −26%, SIM = −16%, LOS + SIM = −28%, p <0.05) more than LOS or SIM alone. Both Rho and matrix metalloprotease-9 (MMP-9) activity in LV tissue were increased in untreated DS rats, and LOS and SIM in combination decreased these changes more than did LOS and SIM monotherapies. We confirmed that the plasma level of Exp-3174 (E3174), a LOS metabolite and a potent inverse agonist of angiotensin II receptor type 1, was higher in rats treated with LOS and SIM in combination than in those treated with LOS alone (E3174/LOS ratio; LOS = 2.6 ± 0.3 vs. LOS + SIM = 3.2 ± 0.2, p <0.05). Next, to mimic the response of volume-overload heart failure in vitro , cultured neonatal rat cardiomyocytes (CMs) were cyclically stretched. Stretch-induced increased CM hypertrophy was suppressed by pretreatment with both SIM and E3174 more than by pretreatment with LOS, E3174, SIM, or LOS and SIM in combination. Mechanical stretch also induced activation of extracellular signal regulated kinase (ERK) and the stretch-induced ERK activation of CMs was also significantly suppressed by SIM + E3174. In conclusion, LOS and SIM had beneficial myocardial effects in rats with salt-sensitive hypertension, partly through promoting the accumulation of plasma E3174. SIM enhanced the myocardial protective effects of LOS through suppression of Rho and MMP-9 activity. Thus, a combination of ARB with statin has a promising potential as a therapeutic strategy for HF.

Abstract P341: Juvenile Exposure To Doxorubicin Differentially Alters The Cardiac Response To Angiotensin II And Isoproterenol In Adult Mice

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Marianne K Grant ◽  
Beshay N Zordoky
Keyword(s):  
Heart Failure ◽  
Risk Factor ◽  
Angiotensin Ii ◽  
Cardiac Function ◽  
Cancer Survivors ◽  
Childhood Cancer ◽  
Significant Risk ◽  
Significant Risk Factor ◽  
Childhood Cancer Survivors ◽  
Cardiac Response

Hypertension is the most significant risk factor for heart failure in doxorubicin (DOX)-treated childhood cancer survivors. We previously developed a two-hit mouse model of juvenile DOX-induced latent cardiotoxicity that is exacerbated by adult-onset angiotensin II (ANGII)-induced hypertension. Nevertheless, it is still not known how juvenile exposure to DOX would predispose the heart to other cardiovascular pathologic stimuli that do not cause hypertension. The objective of this work was to compare the effects of ANGII to those of isoproterenol (ISO) in adult C57BL6/N mice pre-exposed to DOX as juveniles. Five-week-old male mice were administered a low dose of DOX (4 mg/kg/week) or saline for 3 weeks and then allowed to recover for 5 weeks. Thereafter, mice were either infused with ANGII (1.4 mg/kg/day) or injected with ISO (10 mg/kg/day) for 14 days. Juvenile exposure to DOX abrogated the hypertrophic response to both ANGII and ISO, while it failed to correct ANGII- and ISO-induced upregulation in the hypertrophic markers ANP and BNP. ANGII, but not ISO, worsened cardiac function in DOX-exposed mice as measured by echocardiography. Cardiac fibrosis was also exacerbated by ANGII, but not ISO, in DOX-exposed mice as evident by Masson’s trichrome staining and upregulation of the inflammatory and fibrotic markers, Cox-2, Col1a1, Col3a1 , and galectin-3 . In conclusion, the current work demonstrates that ANGII causes more severe deterioration in cardiac function and adverse cardiac remodeling in DOX-exposed mice when compared to ISO. The comparison between DOX/ANGII and DOX/ISO models is critical to understanding why hypertension is the most significant risk factor for heart failure in DOX-treated childhood cancer survivors and thereby devising effective therapeutic strategies against this significant clinical problem.

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