Double trouble: combined cardiovascular effects of particulate matter exposure and coronavirus disease 2019.

The coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly grown into a pandemic. According to initial reports, the lungs were thought to be the primary target, but recent case studies have shown its reach can extend to other organs including the heart and blood vessels. The severity of cardiac complications of COVID-19 depends on multiple underlying factors, with air pollutant exposure being one of them, as reported by several recent studies. Airborne particulate matter (PM) attracts heightened attention due to its implication in various diseases, especially respiratory and cardiovascular diseases. Inhaled PM not only carries microorganisms inside the body but also elicits local and systemic inflammatory responses resulting in altering the host's immunity and increasing susceptibility to infection. Previous and recent studies have documented that PM acts as a 'carrier' for the virus and aids in spreading viral infections. This review presents the mechanisms and effects of viral entry and how pollution can potentially modulate pathophysiological processes in the heart. We aimed to concisely summarize studies examining cardiovascular outcomes in COVID-19 patients and postulate on how PM can influence these outcomes. We have also reviewed evidence on the use of renin-angiotensin system inhibitors, namely angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, in patients with COVID-19. The interplay of pollution and SARS-CoV-2 is essential to understanding the effects of accentuated cardiovascular effects of COVID-19 and deserves in-depth experimental investigations.

Cardiovascular risk of electronic cigarettes: a review of preclinical and clinical studies.

Cigarette smoking is the most preventable risk factor related to cardiovascular morbidity and mortality. Tobacco usage has declined in recent years; however, the use of alternative nicotine delivery methods, particularly e-cigarettes, has increased exponentially despite limited data on their short- and long-term safety and efficacy. Due to their unique properties, the impact of e-cigarettes on cardiovascular physiology is not fully known. Here, we summarize both preclinical and clinical data extracted from short- and long-term studies on the cardiovascular effects of e-cigarette use. Current findings support that e-cigarettes are not a harm-free alternative to tobacco smoke. However, the data are primarily derived from acute studies. The impact of chronic e-cigarette exposure is essentially unstudied. To explore the uniqueness of e-cigarettes, we contemplate the cardiovascular effects of individual e-cigarette constituents. Overall, data suggest that exposure to e-cigarettes could be a potential cardiovascular health concern. Further preclinical research and randomized trials are needed to expand basic and clinical investigations before considering e-cigarettes safe alternatives to conventional cigarettes.

Exercise does not ameliorate cardiac dysfunction in obese mice exposed to fine particulate matter.

BACKGROUND: Studies have demonstrated that exposure to fine particulate matter (PM2.5) is linked to cardiovascular disease (CVD), which is exacerbated in patients with pre-existing conditions such as obesity. In the present study, we examined cardiac function of obese mice exposed to PM2.5 and determined if mild exercise affected cardiac function. METHODS: Obese mice (ob/ob) (leptin deficient, C57BL/6J background) were exposed to either filtered air (FA) or PM2.5 at an average concentration of 32 µg/m3 for 6 h/day, 5 days/week for 9 months. Following exposure, mice were divided into four groups: (1) FA sedentary, (2) FA treadmill exercise, (3) PM2.5 sedentary, and (4) PM2.5 treadmill exercise and all mice were analyzed after 8 weeks of exercise training. RESULTS: Echocardiography showed increased left ventricular end systolic (LVESd) and diastolic (LVEDd) diameters in PM2.5 sedentary mice compared to FA sedentary mice. There was increased expression of ICAM1, VCAM and CRP markers in sedentary PM2.5 mice compared to FA mice. Both FA and PM2.5 exercised mice showed decreased posterior wall thickness in systole compared to FA sedentary mice, coupled with altered expression of inflammatory markers following exercise. CONCLUSION: Obese mice exposed to PM2.5 for 9 months showed cardiac dysfunction, which was not improved following mild exercise training.

Preconception Exposure to Fine Particulate Matter Leads to Cardiac Dysfunction in Adult Male Offspring.

Background Particulate matter (particles < 2.5 µm [ PM 2.5]) exposure during the in utero and postnatal developmental periods causes cardiac dysfunction during adulthood. Here, we investigated the potential priming effects of preconception exposure of PM 2.5 on cardiac function in adult offspring. Methods and Results Male and female friend leukemia virus b (FVB) mice were exposed to either filtered air ( FA ) or PM 2.5 at an average concentration of 38.58 µg/m3 for 6 hours/day, 5 days/week for 3 months. Mice were then crossbred into 2 groups: (1)  FA male× FA female (both parents were exposed to FA preconception) and, (2) PM 2.5male× PM 2.5female (both parents were exposed to PM 2.5 preconception). Male offspring were divided: (1) preconception FA (offspring born to FA exposed parents) and, (2) preconception PM 2.5 (offspring born to PM 2.5 exposed parents) and analyzed at 3 months of age. Echocardiography identified increased left ventricular end systolic volume and reduced posterior wall thickness, reduced %fractional shortening and %ejection fraction in preconception PM 2.5 offspring. Cardiomyocytes isolated from preconception PM 2.5 offspring showed reduced %peak shortening, -dL/dT, TPS 90 and slower calcium reuptake (tau). Gene and protein expression revealed modifications in markers of inflammation ( IL -6, IL -15, TNF α, NF қB, CRP , CD 26E, CD 26P, intercellular adhesion molecule 1, and monocyte chemoattractant protein-1) profibrosis (collagen type III alpha 1 chain), oxidative stress ( NOS 2), antioxidants (Nrf2, SOD , catalase), Ca2+ regulatory proteins ( SERCA 2a, p- PLN , NCX ), and epigenetic regulators (Dnmt1, Dnmt3a, Dnmt3b, Sirt1, and Sirt2) in preconception PM 2.5 offspring. Conclusions Preconception exposure to PM 2.5 results in global cardiac dysfunction in adult offspring, suggesting that abnormalities during development are not limited to the prenatal or postnatal periods but can also be determined before conception.

In utero exposure to fine particulate matter results in an altered neuroimmune phenotype in adult mice.

Environmental exposure to air pollution has been linked to a number of health problems including organ rejection, lung damage and inflammation. While the deleterious effects of air pollution in adult animals are well documented, the long-term consequences of particulate matter (PM) exposure during animal development are uncertain. In this study we tested the hypothesis that environmental exposure to PM 2.5 µm in diameter in utero promotes long term inflammation and neurodegeneration. We evaluated the behavior of PM exposed animals using several tests and observed deficits in spatial memory without robust changes in anxiety-like behavior. We then examined how this affects the brains of adult animals by examining proteins implicated in neurodegeneration, synapse formation and inflammation by western blot, ELISA and immunohistochemistry. These tests revealed significantly increased levels of COX2 protein in PM2.5 exposed animal brains in addition to changes in synaptophysin and Arg1 proteins. Exposure to PM2.5 also increased the immunoreactivity for GFAP, a marker of activated astrocytes. Cytokine concentrations in the brain and spleen were also altered by PM2.5 exposure. These findings indicate that in utero exposure to particulate matter has long term consequences which may affect the development of both the brain and the immune system in addition to promoting inflammatory change in adult animals.

Cardiac pathophysiology in response to environmental stress: a current review.

PURPOSE: Environmental stressors are disturbing our ecosystem at an accelerating rate. An increasingly relevant stressor are air pollutants, whose levels are increasing worldwide with threats to human health. These air pollutants are associated with increased mortality and morbidity from cardiovascular diseases. In this review we discuss environmental stressors focusing mainly on the various types of air pollutants, their short-term and long-term cardiovascular effects, and providing the epidemiological evidence associated with adverse cardiovascular outcomes. Direct and indirect pathophysiological mechanisms are also linked with cardiovascular complications such as thrombosis, fibrinolysis, hypertension, ischemic heart diseases and arrhythmias. RESULTS: Evidence to date suggests that humans are constantly being exposed to unhealthy levels of environmental toxicants with the potential of serious health conditions. Environmental stressors adversely affect the cardiovascular system and pose an increased risk for cardiovascular diseases for those who reside in highly polluted areas. CONCLUSION: People with existing risk factors and those with established cardiovascular disease have increased susceptibility to environmental stressors. The literature reviewed in this article thus support public health policies aimed at reducing pollutant exposure to benefit public health.

PM2.5 exposure in utero contributes to neonatal cardiac dysfunction in mice.

OBJECTIVE: Exposure of fine particulate matter (PM2.5) to pregnant dams has been shown to be strongly associated with adverse cardiovascular outcomes in offspring at adulthood, however, effects evident during neonatal periods are unclear. We designed this study to examine cardiac function of neonatal mice (14 days old) exposed to in utero PM2.5. METHODS: Pregnant FVB female mice were exposed either to filtered air (FA) or PM2.5 at an average concentration of 91.78 µg/m3 for 6 h/day, 5 days/wk (similar to exposure in a large industrial area) throughout the gestation period (21 days). After birth, animals were analyzed at day 14 of life. RESULTS: Fourteen day old mice exposed to PM2.5 during the in utero period demonstrated decreased fractional shortening (%FS, 41.1 ± 1.2% FA, 33.7 ± 1.2% PM2.5, p < 0.01) and LVEDd (2.87 ± 0.08 mm FA, 2.58 ± 0.07 mm PM2.5, p < 0.05) compared to FA exposed mice. Contractile kinetics and calcium transients in isolated cardiomyocytes from PM2.5 exposed mice illustrated reduced peak shortening (%PS, 16.7 ± 0.5% FA, 14.7 ± 0.4% PM2.5, p < 0.01), negative contractile velocity (-dL/dT, -6.91 ± 0.3 µm/s FA, -5.46 ± 0.2 µm/s PM2.5, p < 0.001), increased time to relaxation 90% (TR90, 0.07 ± 0.003 s FA, 0.08 ± 0.004 s PM2.5, p < 0.05), decreased calcium transient amplitude (Δ340/380, 33.8 ± 3.4 FA, 29.5 ± 2.8 p.m.2.5) and slower fluorescence decay rate (τ, 0.72 ± 0.1 s FA, 1.16 ± 0.15 s PM2.5, p < 0.05). Immunoblotting studies demonstrated alterations in expression of Ca2+ handling proteins- SERCA-2A, p-PLN, NCX and CaV1.2 in hearts of 14 day old in utero PM2.5 exposed mice compared to FA exposed hearts. CONCLUSION: PM2.5 exposure during the critical in utero period adversely affects the developing mouse fetus leading to functional cardiac changes that were evident during the very early (14 days) stages of adolescence. These data demonstrated that exposure to PM2.5 during the gestation period significantly impacts cardiovascular outcomes early in life.

In Utero Particulate Matter Exposure Produces Heart Failure, Electrical Remodeling, and Epigenetic Changes at Adulthood.

BACKGROUND: Particulate matter (PM; PM2.5 [PM with diameters of <2.5 µm]) exposure during development is strongly associated with adverse cardiovascular outcomes at adulthood. In the present study, we tested the hypothesis that in utero PM2.5 exposure alone could alter cardiac structure and function at adulthood. METHODS AND RESULTS: Female FVB mice were exposed either to filtered air or PM2.5 at an average concentration of 73.61 µg/m3 for 6 h/day, 7 days/week throughout pregnancy. After birth, animals were analyzed at 12 weeks of age. Echocardiographic (n=9-10 mice/group) and pressure-volume loop analyses (n=5 mice/group) revealed reduced fractional shortening, increased left ventricular end-systolic and -diastolic diameters, reduced left ventricular posterior wall thickness, end-systolic elastance, contractile reserve (dP/dtmax/end-systolic volume), frequency-dependent acceleration of relaxation), and blunted contractile response to ß-adrenergic stimulation in PM2.5-exposed mice. Isolated cardiomyocyte (n=4-5 mice/group) function illustrated reduced peak shortening, ±dL/dT, and prolonged action potential duration at 90% repolarization. Histological left ventricular analyses (n=3 mice/group) showed increased collagen deposition in in utero PM2.5-exposed mice at adulthood. Cardiac interleukin (IL)-6, IL-1ß, collagen-1, matrix metalloproteinase (MMP) 9, and MMP13 gene expressions were increased at birth in in utero PM2.5-exposed mice (n=4 mice/group). In adult hearts (n=5 mice/group), gene expressions of sirtuin (Sirt) 1 and Sirt2 were decreased, DNA methyltransferase (Dnmt) 1, Dnmt3a, and Dnmt3b were increased, and protein expression (n=6 mice/group) of Ca2+-ATPase, phosphorylated phospholamban, and Na+/Ca2+ exchanger were decreased. CONCLUSIONS: In utero PM2.5 exposure triggers an acute inflammatory response, chronic matrix remodeling, and alterations in Ca2+ handling proteins, resulting in global adult cardiac dysfunction. These results also highlight the potential involvement of epigenetics in priming of adult cardiac disease.

Gremlin 2 promotes differentiation of embryonic stem cells to atrial fate by activation of the JNK signaling pathway.

The bone morphogenetic protein antagonist Gremlin 2 (Grem2) is required for atrial differentiation and establishment of cardiac rhythm during embryonic development. A human Grem2 variant has been associated with familial atrial fibrillation, suggesting that abnormal Grem2 activity causes arrhythmias. However, it is not known how Grem2 integrates into signaling pathways to direct atrial cardiomyocyte differentiation. Here, we demonstrate that Grem2 expression is induced concurrently with the emergence of cardiovascular progenitor cells during differentiation of mouse embryonic stem cells (ESCs). Grem2 exposure enhances the cardiogenic potential of ESCs by 20-120-fold, preferentially inducing genes expressed in atrial myocytes such as Myl7, Nppa, and Sarcolipin. We show that Grem2 acts upstream to upregulate proatrial transcription factors CoupTFII and Hey1 and downregulate atrial fate repressors Irx4 and Hey2. The molecular phenotype of Grem2-induced atrial cardiomyocytes was further supported by induction of ion channels encoded by Kcnj3, Kcnj5, and Cacna1d genes and establishment of atrial-like action potentials shown by electrophysiological recordings. We show that promotion of atrial-like cardiomyocytes is specific to the Gremlin subfamily of BMP antagonists. Grem2 proatrial differentiation activity is conveyed by noncanonical BMP signaling through phosphorylation of JNK and can be reversed by specific JNK inhibitors, but not by dorsomorphin, an inhibitor of canonical BMP signaling. Taken together, our data provide novel mechanistic insights into atrial cardiomyocyte differentiation from pluripotent stem cells and will assist the development of future approaches to study and treat arrhythmias.

Functional modeling in zebrafish demonstrates that the atrial-fibrillation-associated gene GREM2 regulates cardiac laterality, cardiomyocyte differentiation and atrial rhythm.

Atrial fibrillation (AF) is the most common cardiac arrhythmia and carries a significant risk of stroke and heart failure. The molecular etiologies of AF are poorly understood, leaving patients with limited therapeutic options. AF has been recognized as an inherited disease in almost 30% of patient cases. However, few genetic loci have been identified and the mechanisms linking genetic variants to AF susceptibility remain unclear. By sequencing 193 probands with lone AF, we identified a Q76E variant within the coding sequence of the bone morphogenetic protein (BMP) antagonist gremlin-2 (GREM2) that increases its inhibitory activity. Functional modeling in zebrafish revealed that, through regulation of BMP signaling, GREM2 is required for cardiac laterality and atrial differentiation during embryonic development. GREM2 overactivity results in slower cardiac contraction rates in zebrafish, and induction of previously identified AF candidate genes encoding connexin-40, sarcolipin and atrial natriuretic peptide in differentiated mouse embryonic stem cells. By live heart imaging in zebrafish overexpressing wild-type or variant GREM2, we found abnormal contraction velocity specifically in atrial cardiomyocytes. These results implicate, for the first time, regulators of BMP signaling in human AF, providing mechanistic insights into the pathogenesis of the disease and identifying potential new therapeutic targets.

Crocus sativus L. (saffron) attenuates isoproterenol-induced myocardial injury via preserving cardiac functions and strengthening antioxidant defense system.

Saffron (dried stigmas of Crocus sativus L.), a naturally derived plant product, has long been used as a traditional ancient medicine against various human diseases. The aim of the series of experiments was to systematically determine whether saffron exerts cardioprotection in isoproterenol-induced myocardial damage. Male Wistar rats (150-175 g) were divided into five groups: control, isoproterenol (ISO) and three saffron (200, 400 and 800 mg/kg) treatment groups. Aqueous extract of saffron or vehicle was administered orally to rats for four weeks. On days 28 and 29, the animals in ISO and saffron treatment groups were administered ISO (85 mg/kg, s.c.) at an interval of 24 h. On day 30, after recording hemodynamics and left ventricular functions, animals were sacrificed for biochemical, histopathological and electromicroscopical examinations. Isoproterenol challenged animals showed depressed hemodynamics and left ventricular functions as evident by decreased left ventricular rate of peak positive and negative pressure change and elevated left ventricular end-diastolic pressure. Structural and ultrastructural studies further confirmed the damage which was reconfirmed by increased thiobarbituric acid reactive substances (p<0.001) and decreased creatine kinase-MB and lactate dehydrogenase (p<0.001). In addition, significant reduction in superoxide dismutase and catalase (p<0.001) was observed in ISO group. Our results suggested that saffron at all the doses exerted significant cardioprotective effect by preserving hemodynamics and left ventricular functions, maintaining structural integrity and augmenting antioxidant status. Among the different doses used, saffron at 400mg/kg dose exhibited maximum protective effects which could be due to maintenance of the redox status of the cell reinforcing its role as an antioxidant.

Curcumin protects rat myocardium against isoproterenol-induced ischemic injury: attenuation of ventricular dysfunction through increased expression of Hsp27 along with strengthening antioxidant defense system.

This investigation examines the role of heat shock protein (Hsp) 27 and its modulation by curcumin in isoproterenol-induced myocardial ischemic injury in rats. Evidence from hemodynamic functions and oxidative stress parameters were also included in the study. The animals were divided into control, isoproterenol, and curcumin 100, 200, and 400 mg/kg treatment groups. Curcumin was administered orally for 15 days to all the treated groups. On 13th and 14th day, isoproterenol (85 mg/kg, s.c.) was injected to curcumin-treated and isoproterenol group. On day 15, hemodynamic parameters were recorded. Thereafter, animals were sacrificed and hearts were kept for biochemical and Western blot analysis. We found dose-dependent increase in the expression of Hsp27 with drastic fall at highest dose. Hemodynamically, the lower 2 doses also restored the cardiac function as evident by improved contractile functions, decreased left ventricular end-diastolic pressure, restored arterial pressures, and heart rate. In addition, there was an increase in then level of superoxide dismutase, catalase, reduced glutathione, and decreased production of thiobarbituric acid reactive substances and leakage of cardiac necroenzyme creatine kinase-MB isoenzyme and lactate dehydrogenase in curcumin 100 and 200 mg/kg group as compared with isoproterenol. However, at a dose of 400 mg/kg, there was ineffectual protection against isoproterenol-induced myocardial damage. Our results suggested 200 mg/mg as the most optimum therapeutic dose showing improved cardiac function due to stabilization of cytoskeleton structure which in turn is attributed to Hsp27 expression along with fortified antioxidant defense system.

Dose-dependent actions of curcumin in experimentally induced myocardial necrosis: a biochemical, histopathological, and electron microscopic evidence.

Curcumin, an active component of turmeric, is a well-known antioxidant due to its reactive oxygen species (ROS) scavenging property. However, some in vitro studies have suggested that curcumin induces generation of ROS at higher doses and thus exerts pro-oxidant effect. We demonstrate, for the first time, the dose-dependent effects of curcumin in isoprenaline-induced model of myocardial necrosis in rats. The animals were assigned to control, isoprenaline and three curcumin treatment groups. Curcumin (100, 200, and 400 mg/kg) and vehicle (dimethyl sulfoxide) were administrated orally for 15 days and isoprenaline (85 mg/kg, s.c.) was given to curcumin treated and isoprenaline group on 13th and 14th day, respectively. Thereafter, on 15th day, the animals were sacrificed for biochemical analysis along with histopathological and ultrastructural examination. There was an increase in glutathione, superoxide dismutase (SOD), creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH) levels, decrease in thiobarbituric acid reactive substances (TBARS), and preservation of myocardial architecture in the curcumin (100 and 200 mg/kg) treated groups. However, at 400 mg/kg dose there was ineffectual protection against isoprenaline-induced myocardial damage. Instead, there was significant lipid peroxidation as evident by increased levels of TBARS (93.87 +/- 9.93, p < 0.0001) and decrease in CK-MB (206.32 +/- 13.54, p < 0.0001) and LDH (134.26 +/- 9.13, p < 0.01) as compared to the two lower doses. Hence, it can be concluded that curcumin augments endogenous antioxidant system at lower doses but mediates ROS induction at higher concentration leading to myocardial damage.