Atrial fibrillation (AF) is the most common clinically relevant arrhythmia, but the methods available for treating AF and its complications (of which the most important is thrombogenesis), as well as ...for assessing AF risk and underlying pathophysiology, are largely limited. Emerging evidence suggests a significant role of inflammation in the pathogenesis of AF. That evidence includes elevated serum levels of inflammatory biomarkers in AF subjects, the expression of inflammatory markers in cardiac tissues of AF patients and animal models of AF, and beneficial effects of anti-inflammatory drugs in experimental AF paradigms. Inflammation is suggested to be linked to various pathological processes, such as oxidative stress, apoptosis, and fibrosis, that promote AF substrate formation. Inflammation has also been associated with endothelial dysfunction, platelet activation, and coagulation cascade activation, leading to thrombogenesis. Thus, inflammation may contribute to both the occurrence/maintenance of AF and its thromboembolic complications. Here, we review the evidence for a role of inflammation and inflammatory biomarkers in the risk management and treatment of AF. We also summarize the current knowledge of inflammation-dependent cellular and molecular mechanisms in AF pathophysiology and their potential as therapeutic targets. (Circ J 2015; 79: 495–502)
Key points
Hyperammonaemia occurs in hepatic, cardiac and pulmonary diseases with increased muscle concentration of ammonia.
We found that ammonia results in reduced skeletal muscle mitochondrial ...respiration, electron transport chain complex I dysfunction, as well as lower NAD+/NADH ratio and ATP content.
During hyperammonaemia, leak of electrons from complex III results in oxidative modification of proteins and lipids.
Tricarboxylic acid cycle intermediates are decreased during hyperammonaemia, and providing a cell‐permeable ester of αKG reversed the lower TCA cycle intermediate concentrations and increased ATP content.
Our observations have high clinical relevance given the potential for novel approaches to reverse skeletal muscle ammonia toxicity by targeting the TCA cycle intermediates and mitochondrial ROS.
Ammonia is a cytotoxic metabolite that is removed primarily by hepatic ureagenesis in humans. Hyperammonaemia occurs in advanced hepatic, cardiac and pulmonary disease, and in urea cycle enzyme deficiencies. Increased skeletal muscle ammonia uptake and metabolism are the major mechanism of non‐hepatic ammonia disposal. Non‐hepatic ammonia disposal occurs in the mitochondria via glutamate synthesis from α‐ketoglutarate resulting in cataplerosis. We show skeletal muscle mitochondrial dysfunction during hyperammonaemia in a comprehensive array of human, rodent and cellular models. ATP synthesis, oxygen consumption, generation of reactive oxygen species with oxidative stress, and tricarboxylic acid (TCA) cycle intermediates were quantified. ATP content was lower in the skeletal muscle from cirrhotic patients, hyperammonaemic portacaval anastomosis rat, and C2C12 myotubes compared to appropriate controls. Hyperammonaemia in C2C12 myotubes resulted in impaired intact cell respiration, reduced complex I/NADH oxidase activity and electron leak occurring at complex III of the electron transport chain. Consistently, lower NAD+/NADH ratio was observed during hyperammonaemia with reduced TCA cycle intermediates compared to controls. Generation of reactive oxygen species resulted in increased content of skeletal muscle carbonylated proteins and thiobarbituric acid reactive substances during hyperammonaemia. A cell‐permeable ester of α‐ketoglutarate reversed the low TCA cycle intermediates and ATP content in myotubes during hyperammonaemia. However, the mitochondrial antioxidant MitoTEMPO did not reverse the lower ATP content during hyperammonaemia. We provide for the first time evidence that skeletal muscle hyperammonaemia results in mitochondrial dysfunction and oxidative stress. Use of anaplerotic substrates to reverse ammonia‐induced mitochondrial dysfunction is a novel therapeutic approach.
Key points
Hyperammonaemia occurs in hepatic, cardiac and pulmonary diseases with increased muscle concentration of ammonia.
We found that ammonia results in reduced skeletal muscle mitochondrial respiration, electron transport chain complex I dysfunction, as well as lower NAD+/NADH ratio and ATP content.
During hyperammonaemia, leak of electrons from complex III results in oxidative modification of proteins and lipids.
Tricarboxylic acid cycle intermediates are decreased during hyperammonaemia, and providing a cell‐permeable ester of αKG reversed the lower TCA cycle intermediate concentrations and increased ATP content.
Our observations have high clinical relevance given the potential for novel approaches to reverse skeletal muscle ammonia toxicity by targeting the TCA cycle intermediates and mitochondrial ROS.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
A surge of data has reproducibly identified strong associations of OSA with cardiac arrhythmias. As an extension of epidemiologic and clinic-based findings, experimental investigations have made ...strides in advancing our understanding of the putative OSA and cardiac arrhythmogenesis mechanistic underpinnings. Although most studies have focused on the links between OSA and atrial fibrillation (AF), relationships with ventricular arrhythmias have also been characterized. Key findings implicate OSA-related autonomic nervous system fluctuations typified by enhanced parasympathetic activation during respiratory events and sympathetic surges subsequent to respiratory events, which contribute to augmented arrhythmic propensity. Other more immediate pathophysiologic influences of OSA-enhancing arrhythmogenesis include intermittent hypoxia, intrathoracic pressure swings leading to atrial stretch, and hypercapnia. Intermediate pathways by which OSA may trigger arrhythmia include increased systemic inflammation, oxidative stress, enhanced prothrombotic state, and vascular dysfunction. Long-term OSA-associated sequelae such as hypertension, atrial enlargement and fibrosis, ventricular hypertrophy, and coronary artery disease also predispose to cardiac arrhythmia. These factors can lead to a reduction in atrial effective refractory period, triggered and abnormal automaticity, and promote slowed and heterogeneous conduction; all of these mechanisms increase the persistence of reentrant arrhythmias and prolong the QT interval. Cardiac electrical and structural remodeling observed in OSA animal models can progress the arrhythmogenic substrate to further enhance arrhythmia generation. Future investigations clarifying the contribution of specific OSA-related mechanistic pathways to arrhythmia generation may allow targeted preventative therapies to mitigate OSA-induced arrhythmogenicity. Furthermore, interventional studies are needed to clarify the impact of OSA pathophysiology reversal on cardiac arrhythmogenesis and related adverse outcomes.
The presence of systemic inflammation determined by elevations in C-reactive protein (CRP) has been associated with persistence of atrial fibrillation (AF). The relationship between CRP and ...prediction of AF has not been studied in a large population-based cohort.
CRP measurement and cardiovascular assessment were performed at baseline in 5806 subjects enrolled in the Cardiovascular Health Study. Patients were followed up for a mean of 6.9+/-1.6 (median 7.8) years. AF was identified by self-reported history and ECGs at baseline and by ECGs and hospital discharge diagnoses at follow-up. Univariate and multivariate analyses were used to assess CRP as a predictor of baseline and future development of AF. At baseline, 315 subjects (5%) had AF. Compared with subjects in the first CRP quartile (<0.97 mg/L), subjects in the fourth quartile (>3.41 mg/L) had more AF (7.4% versus 3.7%, adjusted OR 1.8, 95% CI 1.2 to 2.5; P=0.002). Of 5491 subjects without AF at baseline, 897 (16%) developed AF during follow-up. Baseline CRP predicted higher risk for developing future AF (fourth versus first quartile adjusted hazard ratio 1.31, 95% CI 1.08 to 1.58; P=0.005). When treated as a continuous variable, elevated CRP predicted increased risk for developing future AF (adjusted hazard ratio for 1-SD increase, 1.24; 95% CI 1.11 to 1.40; P<0.001).
CRP is not only associated with the presence of AF but may also predict patients at increased risk for future development of AF.
Atrial fibrillation (AF) is an important cause of stroke and risk factor for heart failure and death. Current pharmacologic treatments for AF have limited efficacy, and treatments that more directly ...target the underlying causes of AF are needed. Oxidant stress and inflammatory activation are interrelated pathways that promote atrial electrical and structural remodeling, leading to atrial ectopy, interstitial fibrosis, and increased stroke risk. This review evaluates the impact of common stressors on atrial oxidant stress and inflammatory activation and the contribution of these pathways to atrial remodeling. Recent studies suggest that integrated efforts to target the underlying risk factors, rather than the AF per se, may have a greater impact on health and outcomes than isolated efforts focused on the electrical abnormalities.
Graphical Abstract
Graphical Abstract
Atrial contractility is regulated by intracellular calcium levels; these reflect the balance of calcium influx, sequestration, and efflux. Beta-adrenergic ...activation with either norepinephrine (endogenous) or isoproterenol (pharmacological) increases the activity of adenylate cyclase, increasing cAMP levels and protein kinase A (PKA) activity. Degradation of cAMP is regulated by phosphodiesterases (PDEs). The phosphorylation state of relevant PKA targets, such as the L-type calcium channel (LTCC), the sarcoplasmic reticulum Ca2+-ATPase (SERCA2a), and myofilament proteins, is regulated by the balance of PKA activity and phosphatase activity. In patients with no history of atrial fibrillation (AF) or paroxysmal AF (pAF), basal phosphorylation of key LTCC subunits is higher than in atrial myocytes from patients with chronic (persistent) AF.14 Pavlidou et al.14 provide novel evidence that this is probably due to increased abundance and activity of phosphodiesterase isoform 8B, variant 2 (PDE8B2), in patients with chronic AF.
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