Oxidative stress and heart failure Tsutsui, Hiroyuki; Kinugawa, Shintaro; Matsushima, Shouji
American journal of physiology. Heart and circulatory physiology
301, Številka:
6
Journal Article
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Oxidative stress, defined as an excess production of reactive oxygen species (ROS) relative to antioxidant defense, has been shown to play an important role in the pathophysiology of cardiac ...remodeling and heart failure (HF). It induces subtle changes in intracellular pathways, redox signaling, at lower levels, but causes cellular dysfunction and damage at higher levels. ROS are derived from several intracellular sources, including mitochondria, NAD(P)H oxidase, xanthine oxidase, and uncoupled nitric oxide synthase. The production of ROS is increased within the mitochondria from failing hearts, whereas normal antioxidant enzyme activities are preserved. Chronic increases in ROS production in the mitochondria lead to a catastrophic cycle of mitochondrial DNA (mtDNA) damage as well as functional decline, further ROS generation, and cellular injury. ROS directly impair contractile function by modifying proteins central to excitation-contraction coupling. Moreover, ROS activate a broad variety of hypertrophy signaling kinases and transcription factors and mediate apoptosis. They also stimulate cardiac fibroblast proliferation and activate the matrix metalloproteinases, leading to the extracellular matrix remodeling. These cellular events are involved in the development and progression of maladaptive myocardial remodeling and failure. Oxidative stress is also involved in the skeletal muscle dysfunction, which may be associated with exercise intolerance and insulin resistance in HF. Therefore, oxidative stress is involved in the pathophysiology of HF in the heart as well as in the skeletal muscle. A better understanding of these mechanisms may enable the development of novel and effective therapeutic strategies against HF.
Inflammatory cardiomyopathy, characterized by inflammatory cell infiltration into the myocardium and a high risk of deteriorating cardiac function, has a heterogeneous aetiology. Inflammatory ...cardiomyopathy is predominantly mediated by viral infection, but can also be induced by bacterial, protozoal or fungal infections as well as a wide variety of toxic substances and drugs and systemic immune-mediated diseases. Despite extensive research, inflammatory cardiomyopathy complicated by left ventricular dysfunction, heart failure or arrhythmia is associated with a poor prognosis. At present, the reason why some patients recover without residual myocardial injury whereas others develop dilated cardiomyopathy is unclear. The relative roles of the pathogen, host genomics and environmental factors in disease progression and healing are still under discussion, including which viruses are active inducers and which are only bystanders. As a consequence, treatment strategies are not well established. In this Review, we summarize and evaluate the available evidence on the pathogenesis, diagnosis and treatment of myocarditis and inflammatory cardiomyopathy, with a special focus on virus-induced and virus-associated myocarditis. Furthermore, we identify knowledge gaps, appraise the available experimental models and propose future directions for the field. The current knowledge and open questions regarding the cardiovascular effects associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are also discussed. This Review is the result of scientific cooperation of members of the Heart Failure Association of the ESC, the Heart Failure Society of America and the Japanese Heart Failure Society.
Background:Since cardiovascular disease accounts for one-quarter of deaths in the Japanese population, we developed a nationwide database using the administrative case-mix Diagnostic Procedure ...Combination (DPC) system (ie, theJapaneseRegistryOfAll cardiac and vascularDiseases (JROAD)-DPC) to reveal the current status of cardiovascular medicine in Japan.Methods and Results:The JROAD-DPC database included 704,593 health records’ data of 2012 from 610 certificated hospitals of the Japanese Circulation Society. The 35,824 patients with acute myocardial infarction (AMI) and 108,665 patients with heart failure (HF) were admitted to hospitals. Increased hospital case volume was associated with reduced in-hospital mortality rates for both AMI and HF (P for trend <0.001). Although there was little variation among AMI patients in terms of aspirin use at discharge (median prescription rate, 83.0%; interquartile range IQR, 76.9–88.0%), there were wide variations in the proportions of patients prescribed β-blockers (BB) and angiotensin-converting enzyme inhibitors (ACEI)/angiotensin-receptor blockers (ARB) at discharge (BB, 41.4%, IQR 27.6–55.7%; ACEI/ARB, 52.0%, IQR 40.3–62.3%). In patients with HF, there were between-hospital variations in medications at discharge (BB, 38.1%, IQR, 27.8–47.6%; ACEI/ARB, 41.0%, IQR 31.7–49.1%).Conclusions:A nationwide administrative database of patients with cardiovascular diseases (JROAD-DPC) provided useful information that will contribute to improved quality of medical care, especially in the aging society of Japan, where HF has become an important health problem. (Circ J 2016; 80: 2327–2335)
Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure in patients regardless of the presence or absence of diabetes. More evidence is needed regarding ...the effects of these drugs in patients across the broad spectrum of heart failure, including those with a markedly reduced ejection fraction.
In this double-blind trial, we randomly assigned 3730 patients with class II, III, or IV heart failure and an ejection fraction of 40% or less to receive empagliflozin (10 mg once daily) or placebo, in addition to recommended therapy. The primary outcome was a composite of cardiovascular death or hospitalization for worsening heart failure.
During a median of 16 months, a primary outcome event occurred in 361 of 1863 patients (19.4%) in the empagliflozin group and in 462 of 1867 patients (24.7%) in the placebo group (hazard ratio for cardiovascular death or hospitalization for heart failure, 0.75; 95% confidence interval CI, 0.65 to 0.86; P<0.001). The effect of empagliflozin on the primary outcome was consistent in patients regardless of the presence or absence of diabetes. The total number of hospitalizations for heart failure was lower in the empagliflozin group than in the placebo group (hazard ratio, 0.70; 95% CI, 0.58 to 0.85; P<0.001). The annual rate of decline in the estimated glomerular filtration rate was slower in the empagliflozin group than in the placebo group (-0.55 vs. -2.28 ml per minute per 1.73 m
of body-surface area per year, P<0.001), and empagliflozin-treated patients had a lower risk of serious renal outcomes. Uncomplicated genital tract infection was reported more frequently with empagliflozin.
Among patients receiving recommended therapy for heart failure, those in the empagliflozin group had a lower risk of cardiovascular death or hospitalization for heart failure than those in the placebo group, regardless of the presence or absence of diabetes. (Funded by Boehringer Ingelheim and Eli Lilly; EMPEROR-Reduced ClinicalTrials.gov number, NCT03057977.).
Higher heart rate (HR) is independently related to worse outcomes in various cardiac diseases, including hypertension, coronary artery disease, and heart failure (HF). HR is determined by the ...pacemaker activity of cells within the sinoatrial node. The hyperpolarization-activated cyclic nucleotide-gated (HCN) 4 channel, one of 4 HCN isoforms, generates the If current and plays an important role in the regulation of pacemaker activity in the sinoatrial node. Ivabradine is a novel and only available HCN inhibitor, which can reduce HR and has been approved for stable angina and chronic HF in many countries other than Japan. In this review, we summarize the current knowledge of the HCN4 channel and ivabradine, including the function of HCN4 in cardiac pacemaking, the mechanism of action of If inhibition by ivabradine, and the pharmacological and clinical effects of ivabradine in cardiac diseases as HF, coronary artery disease, and atrial fibrillation.
Background:Ischemic preconditioning (IPC) is an effective procedure to protect against ischemia/reperfusion (I/R) injury. Hypoxia-inducible factor-1α (Hif-1α) is a key molecule in IPC, and roxadustat ...(RXD), a first-in-class prolyl hydroxylase domain-containing protein inhibitor, has been recently developed to treat anemia in patients with chronic kidney disease. Thus, we investigated whether RXD pretreatment protects against I/R injury.Methods and Results:RXD pretreatment markedly reduced the infarct size and suppressed plasma creatinine kinase activity in a murine I/R model. Analysis of oxygen metabolism showed that RXD could produce ischemic tolerance by shifting metabolism from aerobic to anaerobic respiration.Conclusions:RXD pretreatment may be a novel strategy against I/R injury.
Hypertension is associated with systemic inflammation. The activation of the sympathetic nervous system is critically involved in the pathogenesis of hypertension. Brain perivascular macrophages ...(PVMs) can be affected by circulating inflammatory cytokines, and the contribution of brain PVMs to sympathoexcitation has been demonstrated in a heart failure model. We thus investigated whether brain PVMs contribute to the development of hypertension through sympathoexcitation. Stroke-prone spontaneously hypertensive rats (SHRSP) developed hypertension over an 8-week period from 4 to 12 weeks of age. The number of brain PVMs and plasma interleukin-1β levels significantly increased at the ages of 8 and 12 weeks in SHRSP compared with normotensive Wistar-Kyoto rats (WKY). To determine the contribution of brain PVMs to blood pressure elevation, we intracerebroventricularly injected liposome-encapsulated clodronate, which eliminates macrophages by inducing apoptosis, into 8-week-old rats; we then assessed its effects in 10-week-old rats. Clodronate treatment attenuated the increase in mean blood pressure in SHRSP but not in WKY. Clodronate treatment reduced the depressor effect of hexamethonium, an index of sympathetic activity; it also reduced neuronal activity in sympathetic regulatory nuclei such as the hypothalamic paraventricular nucleus and rostral ventrolateral medulla and reduced the expression of cyclooxygenase-2 and prostaglandin E2, a downstream pathway in activated macrophages, in SHRSP but not in WKY. Furthermore, clodronate treatment attenuated the increase in blood pressure and renal sympathetic nerve activity in response to an acute intravenous injection of interleukin-1β in WKY. In conclusion, brain PVMs contribute to the development of hypertension via sympathetic activation. PVMs may be activated by increased levels of circulating interleukin-1β.
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