scholarly journals Ventricular arrhythmia susceptibility in a new porcine model of heart failure (HF) with reduced ejection fraction

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
J Melka ◽  
A Helbert ◽  
L Lesage ◽  
K Moreau ◽  
K Romariz ◽  
...  
Keyword(s):  
Ventricular Fibrillation ◽  
Ejection Fraction ◽  
Ventricular Arrhythmia ◽  
Ventricular Arrhythmias ◽  
Sham Group ◽  
Pig Model ◽  
Vehicle Group ◽  
Electrical Remodeling ◽  
Reduced Ejection Fraction ◽  
Lv Remodeling

Abstract Introduction Sudden death secondary to ventricular arrhythmias is common in HF patients, with no effective treatment available outside of implantable cardiac defibrillators. While animal models are essential for the discovery of anti-arrhythmic drugs, no reliable large animal HF models with associated ventricular arrhythmias have been described so far. Objectives We aimed at evaluating ventricular remodeling and arrhythmia susceptibility in an HF pig model with reduced ejection fraction (EF) following myocardial infarction (MI). Methods MI was induced in 53 male Göttingen minipigs (12–15 months, 20–25 kg) by coronary embolization in mid-left anterior descending and mid-left circumflex coronary arteries using endovascular coils. Seven other pigs underwent sham operation and were used as control. Two weeks after surgery, cardiac function was assessed by echocardiography, and animals were included based on EF<50% (n=15/53), assigned either to 12 weeks of vehicle (n=9) or perindopril (n=6, 1 mg/kg/d, per os) group. At the end of the study, their left ventricular (LV) electrical remodeling was studied by echocardiography/electrocardiography and a programmed-electrical stimulation protocol was performed to evaluate the susceptibility to develop ventricular arrhythmias. Results At the end of the study, animals in the vehicle group had a significant LV remodeling associated with a reduced EF (p<0.05 vs. sham, see table). This remodeling was associated with cardio-pulmonary congestion, significant increases in LV end-diastolic pressure, left atrial volume, and lung mass (all p<0.05 vs. sham, see table), fully prevented by perindopril treatment. They had also an electrical remodeling as evidenced by an increase in PR, QRS, and QTc intervals, as well as LV effective refractory period (+18%, 14%, 33%, and 13%, respectively, p<0.05, compared to sham animals). Electrical changes were mitigated by perindopril treatment (p=NS vs. sham). LV mechanical dispersion measured with speckle-tracking echocardiography was significantly increased in vehicle group (58±5 vs. 22±1 ms in sham group, respectively) as well as in perindopril group. Programmed-electrical stimulations induced in 6/8 vehicle animals either non-sustained (n=3) or sustained (n=2) ventricular tachycardia, or ventricular fibrillation (n=1). In sham group only 1/7 animal had a ventricular fibrillation. No inducible ventricular arrhythmia was observed in animals treated with Perindopril. Conclusion In this new pig model of congestive HF with reduced EF, LV remodeling was associated with electrical remodeling and susceptibility to develop arrhythmias. Chronic angiotensin-converting enzyme inhibitor treatment prevented congestion, mitigated electrical remodeling, and suppressed arrhythmia susceptibility. FUNDunding Acknowledgement Type of funding sources: Private company. Main funding source(s): Servier Research Institute - CardioVascular & Metabolic Diseases Center for Therapeutic Innovation Table 1

Abstract 393: Chronic Nebivolol Treatment Attenuates MMP Activity and Oxidative Stress and Improves Renovascular Hypertension-induced Cardiac Hypertrophy

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Elen R Sanchez ◽  
Carla S Ceron ◽  
Danielle A Gimaraes ◽  
Cibele M Prado ◽  
Alisson Martins-Oliveira ◽  
...  
Keyword(s):  
Cardiac Remodeling ◽  
Structural Changes ◽  
Sham Group ◽  
Antioxidant Properties ◽  
Left Ventricular ◽  
Vehicle Group ◽  
Left Renal Artery ◽  
Similar Reduction ◽  
Lv Remodeling ◽  
Antioxidant Effects

Nebivolol (Nebi) is the most selective cardiac β1-adrenergic receptor blocker and exerts antioxidant effects. Reactive oxygen species (ROS) enhance cardiac matrix metalloproteinase activity (MMPs) and contribute to hypertension-induced left ventricular hypertrophy (LVH). However, it is uncertain whether Nebi decreases MMP-2 levels and cardiac remodeling associated with hypertension as a result of its antioxidant properties. Hypertension was induced by clipping the left renal artery (2K1C). Six weeks after surgery, hypertensive and sham rats were treated with Nebi, Metoprolol (Meto) or Vehicle (by gavage) for four weeks. Systolic blood pressure (SBP) was monitored weekly by tail-cuff plethysmography. LV structural changes were studied in hematoxylin/eosin sections. MMP levels and activity were determined by immunofluorescence and in situ zymography. ROS and nitrotyrosine levels were evaluated by dihydroethidium and immunohistochemistry, respectively. Similar reduction in SBP was found with both treatments (202±5 mmHg in 2K1C+Vehicle versus 161±19 and 162±18 mmHg in 2K1C Nebi or Meto groups, respectively; P<0.05). Both treatments reduced LV remodeling and ROS formation (P<0.05). Both drugs decreased nitrotyrosine levels (3.9±0.2, 2.3±0.3, and 2.4±0.3 arbitrary units, respectively in 2K1C+vehicle, 2K1C+Meto, and 2K1C+Nebi groups, respectively; P<0.05). Increased MMP-2 levels (16.0±2.0 versus 7.0±0.9 arbitrary units; P<0.05) and activity (8.0±0.4 versus 6.0±0.1 arbitrary units; P<0.05) were observed in the 2K1C+vehicle group when compared to the sham group. These alterations were normalized by both treatments (similar levels to those found in the sham group). No significant changes were observed in the sham groups. These findings suggest that different β-blockers exert important antioxidant effects that may underlie the lower LV MMP activity and cardiac remodeling in 2K1C hypertension.

P1603Nicorandil suppresses ischemia-induced cardiac interstitial norepinephrine enhancement and ventricular arrhythmia in hypertrophic hearts

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
M Kobara ◽  
N Naseratun ◽  
Y Watanabe ◽  
H Toba ◽  
T Nakata
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Ventricular Tachycardia ◽  
Ventricular Arrhythmia ◽  
Ventricular Arrhythmias ◽  
Sham Group ◽  
Cardiac Tissue ◽  
Norepinephrine Release ◽  
Norepinephrine Concentration ◽  
Ischemic Period

Abstract Background Myocardial infarction (MI) is a major cause of death in western countries and Japan, and hypertension is a major risk factor of MI. In hypertensive heart, acute myocardial infarction often leads to lethal ventricular arrhythmia. Nicorandil, an ATP sensitive potassium channel (KATP) opener, is usually used in the treatment of acute myocardial infarction. The effects of nicorandil on ischemic myocyte are fully defined. On the other hand, KATP in neuroterminals is known to regulate norepinephrine release, but the effect of nicorandil on ischemic norepinephrine release in cardiac tissue has remained unexplored. Purpose We examined whether nicorandil suppressed norepinephrine release via neuronal KATP and ventricular arrhythmia during acute ischemia in pressure overload-induced hypertrophic hearts. Methods SD Rats were divided into two groups; abdominal aortic constriction (AAC) group and sham-operated (Sham) group. Four weeks after constriction, cardiac geometry and function were examined using echocardiography. Then, myocardial ischemia was induced by the left anterior descending artery occlusion for 100 minutes in the presence or absence of intravenous infusion of nicorandil. Cardiac interstitial norepinephrine concentration in ischemic region was measured using the microdialysis method and concentration of cyclic AMP, a second messenger of norepinephrine, in cardiac tissue was measured by ELISA. Ventricular arrhythmias were monitered by ECG during whole ischemic period. Results Four weeks after constriction, remarkable left ventricular wall thickening was observed in AAC group. Before ischemia, ventricular arrhythmia was not found in both groups. Number of ventricular arrhythmia, including ventricular tachycardia and ventricular fibrillation, was increased in early ischemic period (- 40 min) in both groups, and was grater in AAC group. Before ischemia, interstitial norepinephrine concentration in cardiac tissue was higher level in AAC group than in Sham group. Ischemia obviously increased norepinephrine concentration in both groups time dependently and AAC further increased norepinephrine than Sham group. Concentration of cyclic AMP in cardiac tissue was raised in early ischemic period (- 40 min) and then gradually decreased. Nicorandil significantly suppressed the number of ventricular arrhythmias, and abolished the ventricular tachycardia and fibrillation without hemodynamic alterations. Nicorandil also attenuated norepinephrine and cAMP enhancement in acute ischemic period in both groups. Conclusion Ischemia-induced ventricular arrhythmia was more frequent and severe in hypertrophic hearts and interstitial norepinephrine enhancement may play a role in this ischemic arrhythmia. Nicorandil suppressed ischemia-induced interstitial norepinephrine release by neuronal KATP opening, which attenuated ventricular arrhythmias in normal and hypertrophic hearts.

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