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Targeted antioxidant treatment decreases cardiac alternans associated with chronic myocardial infarction.

ABSTRACT: BACKGROUND:In myocardial infarction (MI), repolarization alternans is a potent arrhythmia substrate that has been linked to Ca2+ cycling proteins, such as sarcoplasmic reticulum Ca2+ ATPase (SERCA2a), located in the sarcoplasmic reticulum. MI is also associated with oxidative stress and increased xanthine oxidase (XO) activity, an important source of reactive oxygen species (ROS) in the sarcoplasmic reticulum that may reduce SERCA2a function. We hypothesize that in chronic MI, XO-mediated oxidation of SERCA2a is a mechanism of cardiac alternans. METHODS AND RESULTS:Male Lewis rats underwent ligation of the left anterior descending coronary artery (n=54) or sham procedure (n=24). At 4 weeks, optical mapping of intracellular Ca2+ and ROS was performed. ECG T-wave alternans (ECG ALT) and Ca2+ transient alternans (Ca2+ALT) were induced by rapid pacing (300-120 ms) before and after the XO inhibitor allopurinol (ALLO, 50 µmol/L). In MI, ECG ALT (2.32±0.41%) and Ca2+ ALT (22.3±4.5%) were significantly greater compared with sham (0.18±0.08%, P<0.001; 0.79±0.32%, P<0.01). Additionally, ROS was increased by 137% (P<0.01) and oxidation of SERCA2a by 30% (P<0.05) in MI compared with sham. Treatment with ALLO significantly decreased ECG ALT (-77±9%, P<0.05) and Ca2+ ALT (-56±7%, P<0.05) and, importantly, reduced ROS (-65%, P<0.01) and oxidation of SERCA2a (-38%, P<0.05). CaMKII inhibition and general antioxidant treatment had no effect on ECG ALT and Ca2+ ALT. CONCLUSIONS:These results demonstrate, for the first time, that in MI, increased ROS from XO is a significant cause of repolarization alternans. This suggests that targeting XO ROS production may be effective at preventing arrhythmia substrates in chronic MI.

SUBMITTER: Plummer BN

PROVIDER: S-EPMC4334735 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Targeted antioxidant treatment decreases cardiac alternans associated with chronic myocardial infarction.

Plummer Bradley N BN Liu Haiyan H Wan Xiaoping X Deschênes Isabelle I Laurita Kenneth R KR

Circulation. Arrhythmia and electrophysiology 20141209 1

<h4>Background</h4>In myocardial infarction (MI), repolarization alternans is a potent arrhythmia substrate that has been linked to Ca2+ cycling proteins, such as sarcoplasmic reticulum Ca2+ ATPase (SERCA2a), located in the sarcoplasmic reticulum. MI is also associated with oxidative stress and increased xanthine oxidase (XO) activity, an important source of reactive oxygen species (ROS) in the sarcoplasmic reticulum that may reduce SERCA2a function. We hypothesize that in chronic MI, XO-mediate ...[more]

PMID: 25491741

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Project description:Elucidation of the physiologically distinct subunits of troponin in 1973 greatly facilitated our understanding of cardiac contraction. Although troponins are expressed in both skeletal and cardiac muscle, there are isoforms of troponin I/T expressed selectively in the heart. By exploiting cardiac-restricted epitopes within these proteins, one of the most successful diagnostic tests to date has been developed: cardiac troponin (cTn) assays. For the past decade, cTn has been regarded as the gold-standard marker for acute myocardial necrosis: the pathological hallmark of acute myocardial infarction (AMI). Whilst cTn is the cornerstone for ruling-out AMI in patients presenting with a suspected acute coronary syndrome (ACS), elevated cTn is frequently observed in those without clinical signs indicative of AMI, often reflecting myocardial injury of 'unknown origin'. cTn is commonly elevated in acute non-ACS conditions, as well as in chronic diseases. It is unclear why these elevations occur; yet they cannot be ignored as cTn levels in chronically unwell patients are directly correlated to prognosis. Paradoxically, improvements in assay sensitivity have meant more differential diagnoses have to be considered due to decreased specificity, since cTn is now more easily detected in these non-ACS conditions. It is important to be aware cTn is highly specific for myocardial injury, which could be attributable to a myriad of underlying causes, emphasizing the notion that cTn is an organ-specific, not disease-specific biomarker. Furthermore, the ability to detect increased cTn using high-sensitivity assays following extreme exercise is disconcerting. It has been suggested troponin release can occur without cardiomyocyte necrosis, contradicting conventional dogma, emphasizing a need to understand the mechanisms of such release. This review discusses basic troponin biology, the physiology behind its detection in serum, its use in the diagnosis of AMI, and some key concepts and experimental evidence as to why cTn can be elevated in chronic diseases.

Project description:PURPOSE:Myocardial infarction (MI) triggers a local inflammatory response which orchestrates cardiac repair and contributes to concurrent neuroinflammation. Angiotensin-converting enzyme (ACE) inhibitor therapy not only attenuates cardiac remodeling by interfering with the neurohumoral system, but also influences acute leukocyte mobilization from hematopoietic reservoirs. Here, we seek to dissect the anti-inflammatory and anti-remodeling contributions of ACE inhibitors to the benefit of heart and brain outcomes after MI. METHODS:C57BL/6 mice underwent permanent coronary artery ligation (n?=?41) or sham surgery (n?=?9). Subgroups received ACE inhibitor enalapril (20 mg/kg, oral) either early (anti-inflammatory strategy; 10 days treatment beginning 3 days prior to surgery; n?=?9) or delayed (anti-remodeling; continuous from 7 days post-MI; n?=?16), or no therapy (n?=?16). Cardiac and neuroinflammation were serially investigated using whole-body macrophage- and microglia-targeted translocator protein (TSPO) PET at 3 days, 7 days, and 8 weeks. In vivo PET signal was validated by autoradiography and histopathology. RESULTS:Myocardial infarction evoked higher TSPO signal in the infarct region at 3 days and 7 days compared with sham (p?<?0.001), with concurrent elevation in brain TSPO signal (+?18%, p?=?0.005). At 8 weeks after MI, remote myocardium TSPO signal was increased, consistent with mitochondrial stress, and corresponding to recurrent neuroinflammation. Early enalapril treatment lowered the acute TSPO signal in the heart and brain by 55% (p?<?0.001) and 14% (p?=?0.045), respectively. The acute infarct signal predicted late functional outcome (r?=?0.418, p?=?0.038). Delayed enalapril treatment reduced chronic myocardial TSPO signal, consistent with alleviated mitochondrial stress. Early enalapril therapy tended to lower TSPO signal in the failing myocardium at 8 weeks after MI (p?=?0.090) without an effect on chronic neuroinflammation. CONCLUSIONS:Whole-body TSPO PET identifies myocardial macrophage infiltration and neuroinflammation after MI, and altered cardiomyocyte mitochondrial density in chronic heart failure. Improved chronic cardiac outcome by enalapril treatment derives partially from acute anti-inflammatory activity with complementary benefits in later stages. Whereas early ACE inhibitor therapy lowers acute neuroinflammation, chronic alleviation is not achieved by early or delayed ACE inhibitor therapy, suggesting a more complex mechanism underlying recurrent neuroinflammation in ischemic heart failure.

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Targeted antioxidant treatment decreases cardiac alternans associated with chronic myocardial infarction.

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Targeted antioxidant treatment decreases cardiac alternans associated with chronic myocardial infarction.

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