We examined the effects of daily repetitive brief (15 min) myocardial ischemia and reperfusion (I͞R) in WT C57͞BL6 and extracellular superoxide dismutase (EC-SOD)-overexpressing mice. In the absence of myocardial necrosis, I͞R resulted in persistent fibrosis in ischemic areas of C57͞BL6 mice associated with persistent global and segmental anterior wall dysfunction. The I͞R protocol induced chemokines (peak 3 days) followed sequentially by infiltration of macrophages and myofibroblasts (5 days). Fibrosis peaked at 7 days and was stable at 28 days despite regression of the chemokine and cellular response. Discontinuation of I͞R at 7 or 28 days led to regression of fibrosis and ventricular dysfunction. In contrast, the EC-SOD mice developed markedly less chemokine induction, cell response, and fibrosis, with no ventricular dysfunction. Reversible fibrosis and ventricular dysfunction are features of human hibernating myocardium. The reduction of the cellular and functional response in EC-SOD mice suggests a role for reactive O 2 in the pathogenesis of ischemic cardiomyopathy.

Large animal models have provided much of the descriptive data regarding the cellular and molecular events in myocardial infarction and repair. The availability of genetically altered mice may provide a valuable tool for specific cellular and molecular dissection of these processes. In this report we compare closed chest models of canine and mouse infarction/reperfusion qualitatively and quantitatively for temporal, cellular, and spatial differences. Much like the canine model, reperfused mouse hearts are associated with marked induction of endothelial adhesion molecules, cytokines, and chemokines. Reperfused mouse infarcts show accelerated replacement of cardiomyocytes by granulation tissue leading to a thin mature scar at 14 days, when the canine infarction is still cellular and evolving. Infarcted mouse hearts demonstrate a robust but transient postreperfusion inflammatory reaction, associated with a rapid up-regulation of interleukin-10 and transforming growth factor-␤. Unlike canine infarcts, infarcted mouse hearts show only transient macrophage infiltration and no significant mast cell accumulation. In correlation, the growth factor for macrophages, M-CSF, shows modest and transient up-regulation in the early days of reperfusion; and the obligate growth factor for mast cells, stem cell factor, SCF, is not induced. In summary, the postinfarction inflammatory response and resultant repair in the mouse heart shares many common characteristics with large mammalian species, but has distinct temporal and qualitative features. These important species-specific differences should be considered when interpreting findings derived from studies using genetically altered mice. For almost a century, experimental models of myocardial infarction have contributed to our understanding of the pathobiology of myocardial infarction. Large animal models have been extensively used to study the mechanisms involved in myocardial injury and repair 1,2 and have significantly contributed to our understanding of the pathological process of myocardial infarction. However, large animal studies have significant limitations in investigating the functional role of specific genes in myocardial ischemia. Recent advances in transgenic and gene targeting approaches have allowed sophisticated manipulations of genes whose functions may be important in injury and repair following myocardial infarction.3 Because of technical and economic considerations, these experiments are largely confined to the mouse. 4,5 To capitalize on these advances in gene targeting technology murine models of experimental myocardial infarction have been developed 6,7 and have been extensively used to dissect the mechanisms involved in ischemic myocardial injury. 8 -10 However, extrapolation of the findings derived from murine experiments to the human pathobiology requires similar disease mechanisms in both species. Despite the widespread use of murine models of myocardial infarction, detailed studies of the cellular and molecular events associated with repair of the mous...

Ischemic heart disease is associated with inflammation, interstitial fibrosis and ventricular dysfunction prior to the development of heart failure. Endocannabinoids and the cannabinoid receptor CB2 have been claimed to be involved, but their potential role in cardioprotection is not well understood. We therefore explored the role of the cannabinoid receptor CB2 during the initial phase of ischemic cardiomyopathy development prior to the onset of ventricular dysfunction or infarction. Wild type and CB2-deficient mice underwent daily brief, repetitive ischemia and reperfusion (I/R) episodes leading to ischemic cardiomyopathy. The relevance of the endocannabinoid-CB2 receptor axis was underscored by the finding that CB2 was upregulated in ischemic wild type cardiomyocytes and that anandamide level was transiently increased during I/R. CB2-deficient mice showed an increased rate of apoptosis, irreversible loss of cardiomyocytes and persistent left ventricular dysfunction 60 days after the injury, whereas wild type mice presented neither morphological nor functional defects. These defects were due to lack of cardiomyocyte protection mechanisms, as CB2-deficient hearts were in contrast to controls unable to induce switch in myosin heavy chain isoforms, antioxidative enzymes and chemokine CCL2 during repetitive I/R. In addition, a prolonged inflammatory response and adverse myocardial remodeling were found in CB2-deficient hearts because of postponed activation of the M2a macrophage subpopulation. Therefore, the endocannabinoid-CB2 receptor axis plays a key role in cardioprotection during the initial phase of ischemic cardiomyopathy development.

Background-The peroxisome proliferators-activated receptor-␣ (PPAR␣), a transcription factor that modulates fatty acid metabolism, regulates substrate preference in the heart. Although in acute ischemia there is a switch in substrate preference from fatty acids to glucose, metabolic gene expression in repetitive ischemia is not well described. In a mouse model of ischemic cardiomyopathy induced by repetitive ischemia/reperfusion (I/R), we postulated that downregulation of PPAR␣ is regulated by reactive oxygen species and is necessary for maintaining contractile function in the heart. Methods and Results-Repetitive closed-chest I/R (15 minutes) was performed daily in C57/BL6 mice, mice overexpressing extracellular superoxide dismutase, and mice treated with the PPAR␣ agonist-WY-14,643. Echocardiography, histology, and candidate gene expression were measured at 3, 5, 7, and 28 days of repetitive I/R and 15 and 30 days after discontinuation of I/R. Repetitive I/R was associated with a downregulation of PPAR␣-regulated genes and both myosin heavy chain isoform transcript levels, which was reversible on discontinuation of I/R. Overexpression of EC-SOD prevented the downregulation of PPAR␣-regulated genes and myosin iso-genes by repetitive I/R. Furthermore, reactivation of PPAR␣ in mice exposed to repetitive I/R worsened contractile function, induced microinfarctions, and increased intramyocardial triglyceride deposition, features suggestive of cardiac lipotoxicity. Conclusions-Metabolic and myosin isoform gene expression in repetitive I/R is mediated by reactive oxygen species.Furthermore, we suggest that downregulation of PPAR␣ in repetitive I/R is an adaptive mechanism that is able to prevent lipotoxicity in the ischemic myocardium.

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Pre-treatment with 1668-thioate attenuated cardiac hypertrophy following pressure overload, possibly by modifying the hypertrophy-induced inflammatory response, thereby reducing cardiac growth and fibrosis as well as delaying loss of cardiac function.

Noncommunicable diseases (NCDs) are fatal for more than 38 million people each year and are thus the main contributors to the global burden of disease accounting for 70% of mortality. The majority of these deaths are caused by cardiovascular disease. The risk of NCDs is strongly associated with exposure to environmental stressors such as pollutants in the air, noise exposure, artificial light at night and climate change, including heat extremes, desert storms and wildfires. In addition to the traditional risk factors for cardiovascular disease such as diabetes, arterial hypertension, smoking, hypercholesterolemia and genetic predisposition, there is a growing body of evidence showing that physicochemical factors in the environment contribute significantly to the high NCD numbers. Furthermore, urbanization is associated with accumulation and intensification of these stressors. This comprehensive expert review will summarize the epidemiology and pathophysiology of environmental stressors with a focus on cardiovascular NCDs. We will also discuss solutions and mitigation measures to lower the impact of environmental risk factors with focus on cardiovascular disease.

Background Myocardial injury and inflammation on cardiac MRI in patients suffering from coronavirus disease 19 (COVID-19) have been described in recent publications. Concurrently, a chronic COVID-19 syndrome (CCS) after COVID-19 infection has been observed manifesting with symptoms like fatigue and exertional dyspnea. Purpose To explore the relationship between CCS and myocardial injury and inflammation as an underlying cause of the persistent complaints in previously healthy individuals. Materials and Methods In this prospective study from January 2021 to April 2021, study participants without known cardiac or pulmonary diseases prior to COVID-19 infection with persisting CCS symptoms like fatigue or exertional dyspnea after convalescence and healthy control participants underwent cardiac MRI. Cardiac MRI protocol included T1 and T2 relaxation times, extracellular volume (ECV), T2 signal intensity ratio, and late gadolinium enhancement (LGE). Student t test, Mann-Whitney U test, and χ 2 test were used for statistical analysis. Results 41 participants with CCS (39±13 years; 18 men) and 42 control participants (39±16 years; 26 men) were evaluated. Median time between initial mild to moderate COVID-19 disease without hospitalization and cardiac MRI was 103 days (interquartile range: 88-158). Troponin T levels were normal. Parameters indicating myocardial inflammation and edema were comparable between participants with CCS and control participants: T1 relaxation time (978±23 ms vs 971±25 ms; P=.17), T2 relaxation time (53±2 ms vs 52±2 ms; P=.47), T2 signal intensity ratio (1.6±0.2 vs 1.6±0.3; P=.10). Visible myocardial edema was present in none of the participants. Three of 41 (7%) participants with CCS demonstrated non-ischemic LGE compared to none in the control group (0 of 42 [0%]; P=.07). None of the participants fulfilled the 2018 Lake Louise criteria for the diagnosis of myocarditis. Conclusion Individuals without hospitalization for COVID-19 and with CCS did not demonstrate signs of active myocardial injury or inflammation on cardiac MRI. See also the editorial by Lima and Bluemke .