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Gene Therapy With Angiotensin-(1-9) Preserves Left Ventricular Systolic Function After Myocardial Infarction.

ABSTRACT: Angiotensin-(1-9) [Ang-(1-9)] is a novel peptide of the counter-regulatory axis of the renin-angiotensin-aldosterone system previously demonstrated to have therapeutic potential in hypertensive cardiomyopathy when administered via osmotic mini-pump. Here, we investigate whether gene transfer of Ang-(1-9) is cardioprotective in a murine model of myocardial infarction (MI).The authors evaluated effects of Ang-(1-9) gene therapy on myocardial structural and functional remodeling post-infarction.C57BL/6 mice underwent permanent left anterior descending coronary artery ligation and cardiac function was assessed using echocardiography for 8 weeks followed by a terminal measurement of left ventricular pressure volume loops. Ang-(1-9) was delivered by adeno-associated viral vector via single tail vein injection immediately following induction of MI. Direct effects of Ang-(1-9) on cardiomyocyte excitation/contraction coupling and cardiac contraction were evaluated in isolated mouse and human cardiomyocytes and in an ex vivo Langendorff-perfused whole-heart model.Gene delivery of Ang-(1-9) reduced sudden cardiac death post-MI. Pressure volume measurements revealed complete restoration of end-systolic pressure, ejection fraction, end-systolic volume, and the end-diastolic pressure volume relationship by Ang-(1-9) treatment. Stroke volume and cardiac output were significantly increased versus sham. Histological analysis revealed only mild effects on cardiac hypertrophy and fibrosis, but a significant increase in scar thickness. Direct assessment of Ang-(1-9) on isolated cardiomyocytes demonstrated a positive inotropic effect via increasing calcium transient amplitude and contractility. Ang-(1-9) increased contraction in the Langendorff model through a protein kinase A-dependent mechanism.Our novel findings showed that Ang-(1-9) gene therapy preserved left ventricular systolic function post-MI, restoring cardiac function. Furthermore, Ang-(1-9) directly affected cardiomyocyte calcium handling through a protein kinase A-dependent mechanism. These data emphasized Ang-(1-9) gene therapy as a potential new strategy in the context of MI.

SUBMITTER: Fattah C

PROVIDER: S-EPMC5158000 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Gene Therapy With Angiotensin-(1-9) Preserves Left Ventricular Systolic Function After Myocardial Infarction.

Fattah Caroline C Nather Katrin K McCarroll Charlotte S CS Hortigon-Vinagre Maria P MP Zamora Victor V Flores-Munoz Monica M McArthur Lisa L Zentilin Lorena L Giacca Mauro M Touyz Rhian M RM Smith Godfrey L GL Loughrey Christopher M CM Nicklin Stuart A SA

Journal of the American College of Cardiology 20161201 24

<h4>Background</h4>Angiotensin-(1-9) [Ang-(1-9)] is a novel peptide of the counter-regulatory axis of the renin-angiotensin-aldosterone system previously demonstrated to have therapeutic potential in hypertensive cardiomyopathy when administered via osmotic mini-pump. Here, we investigate whether gene transfer of Ang-(1-9) is cardioprotective in a murine model of myocardial infarction (MI).<h4>Objectives</h4>The authors evaluated effects of Ang-(1-9) gene therapy on myocardial structural and fun ...[more]

PMID: 27978950

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Project description:ObjectiveTo investigate the association between treatment with an angiotensin receptor blocker and clinical outcomes in patients with ST segment elevation myocardial infarction with preserved left ventricular systolic function.DesignA prospective cohort study using data from a nationwide large scale registry.Setting53 hospitals involved in treatment of acute myocardial infarction in Korea.ParticipantsBetween November 2005 and September 2010, we studied 6698 patients with ST segment elevation myocardial infarction who underwent primary percutaneous coronary intervention and had a left ventricular ejection fraction ≥ 40%.Main outcome measuresCardiac death or myocardial infarction. Patients were divided into an angiotensin receptor blocker group (n=1185), an angiotensin converting enzyme (ACE) inhibitor group (n=4564), and a group who did not receive any renin angiotensin system blocker (n=949). Propensity score matching analysis was also performed.ResultsCardiac death or myocardial infarction occurred in 21 patients (1.8%) in the angiotensin receptor blocker group, 77 patients (1.7%) in the ACE inhibitor group, and 33 patients (3.5%) in the no renin angiotensin system blocker group. After propensity score matching (1175 pairs), there was no significant difference in the rate of cardiac death or myocardial infarction between the angiotensin receptor blocker group and ACE inhibitor group (21 (1.8%) v 23 (2.0%), adjusted hazard ratio 0.65, 95% confidence interval 0.30 to 1.38; P=0.65). The angiotensin receptor blocker group had a lower rate of cardiac death or myocardial infarction than the no renin angiotensin system blocker group in matched populations (803 pairs) (14 (1.7%) v 25 (3.1%), 0.35, 0.14 to 0.90; P=0.03).ConclusionAngiotensin receptor blocker showed beneficial effects comparable with ACE inhibitors in patients with ST segment elevation myocardial infarction with preserved left ventricular systolic function. Angiotensin receptor blockers could be used as an alternative to ACE inhibitors in such patients.

Project description:ObjectiveThe occurrence of intramyocardial hemorrhage (IMH) and microvascular obstruction (MVO) in myocardial infarction (MI), known as severe ischemia/reperfusion injury (IRI), has been associated with adverse remodeling. APT102, a soluble human recombinant ecto-nucleoside triphosphate diphosphohydrolase-1, can hydrolyze extracellular nucleotides to attenuate their prothrombotic and proinflammatory effects. The purpose of this study was to temporally evaluate the therapeutic effect of APT102 on IRI in rats and to elucidate the evolution of IRI in the acute stage using cardiovascular magnetic resonance imaging (CMRI).Materials and methodsFifty-four rats with MI, induced by ligation of the origin of the left anterior descending coronary artery for 60 minutes, were randomly divided into the APT102 (n = 27) or control (n = 27) group. Intravenous infusion of APT102 (0.3 mg/kg) or placebo was administered 15 minutes before reperfusion, and then 24 hours, 48 hours, 72 hours, and on day 4 after reperfusion. CMRI was performed at 24 hours, 48 hours, 72 hours, and on day 5 post-reperfusion using a 7T system and the hearts were collected for histopathological examination. Cardiac function was quantified using cine imaging and IMH/edema using T2 mapping, and infarct/MVO using late gadolinium enhancement.ResultsThe extent of infarction (p < 0.001), edema (p < 0.001), IMH (p = 0.013), and MVO (p = 0.049) was less severe in the APT102 group than in the control group. IMH size at 48 hours was significantly greater than that at 24 hours, 72 hours, and 5 days after reperfusion (all p < 0.001). The left ventricular ejection fraction (LVEF) was significantly greater in the APT102 group than in the control group (p = 0.006). There was a negative correlation between LVEF and IMH (r = -0.294, p = 0.010) and a positive correlation between IMH and MVO (r = 0.392, p < 0.001).ConclusionAPT102 can significantly alleviate damage to the ischemic myocardium and microvasculature. IMH size peaked at 48 hours post reperfusion and IMH is a downstream consequence of MVO. IMH may be a potential therapeutic target to prevent adverse remodeling in MI.

Project description:BackgroundPatients with left ventricular (LV) systolic dysfunction after myocardial infarction are at a high risk of developing heart failure. The addition of neprilysin inhibition to renin angiotensin system inhibition may result in greater attenuation of adverse LV remodeling as a result of increased levels of substrates for neprilysin with vasodilatory, antihypertrophic, antifibrotic, and sympatholytic effects.MethodsWe performed a prospective, multicenter, randomized, double-blind, active-comparator trial comparing sacubitril/valsartan 97/103 mg twice daily with valsartan 160 mg twice daily in patients ≥3 months after myocardial infarction with a LV ejection fraction ≤40% who were taking a renin angiotensin system inhibitor (equivalent dose of ramipril ≥2.5 mg twice daily) and a β-blocker unless contraindicated or intolerant. Patients in New York Heart Association class ≥II or with signs and symptoms of heart failure were excluded. The primary outcome was change from baseline to 52 weeks in LV end-systolic volume index measured using cardiac magnetic resonance imaging. Secondary outcomes included other magnetic resonance imaging measurements of LV remodeling, change in NT-proBNP (N-terminal pro-B-type natriuretic peptide) and high-sensitivity cardiac troponin I, and a patient global assessment of change questionnaire.ResultsFrom July 2018 to June 2019, we randomized 93 patients with the following characteristics: mean age, 60.7±10.4 years; median time from myocardial infarction, 3.6 years (interquartile range, 1.2-7.2); mean LV ejection fraction, 36.8%±7.1%; and median NT-proBNP, 230 pg/mL (interquartile range, 124-404). Sacubitril/valsartan, compared with valsartan, did not significantly reduce LV end-systolic volume index; adjusted between-group difference, -1.9 mL/m2 (95% CI, -4.9 to 1.0); P=0.19. There were no significant between-group differences in NT-proBNP, high-sensitivity cardiac troponin I, LV end-diastolic volume index, left atrial volume index, LV ejection fraction, LV mass index, or patient global assessment of change.ConclusionsIn patients with asymptomatic LV systolic dysfunction late after myocardial infarction, treatment with sacubitril/valsartan did not have a significant reverse remodeling effect compared with valsartan. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03552575.

Dataset Information

Gene Therapy With Angiotensin-(1-9) Preserves Left Ventricular Systolic Function After Myocardial Infarction.

Publications

Gene Therapy With Angiotensin-(1-9) Preserves Left Ventricular Systolic Function After Myocardial Infarction.

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