BackgroundParticulate matter (PM; PM 2.5 [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 PM 2.5 exposure alone could alter cardiac structure and function at adulthood.Methods and ResultsFemale FVB mice were exposed either to filtered air or PM 2.5 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 β‐adrenergic stimulation in PM 2.5‐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 PM 2.5‐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 PM 2.5‐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.ConclusionsIn utero PM 2.5 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.

Particulate matter (PM) exposure induces a pathological response from both the lungs and the cardiovascular system. PM is capable of both manifestation into the lung epithelium and entrance into the bloodstream. Therefore, PM has the capacity for both direct and lung-mediated indirect effects on the heart. In the present studies, we exposed isolated rat cardiomyocytes to ultrafine particulate matter (diesel exhaust particles, DEP) and examined their contractile function and calcium handling ability. In another set of experiments, lung epithelial cells (16HBE14o- or Calu-3) were cultured on permeable supports that allowed access to both the basal (serosal) and apical (mucosal) media; the basal media was used to culture cardiomyocytes to model the indirect, lung-mediated effects of PM on the heart. Both the direct and indirect treatments caused a reduction in contractility as evidenced by reduced percent sarcomere shortening and reduced calcium handling ability measured in field-stimulated cardiomyocytes. Treatment of cardiomyocytes with various anti-oxidants before culture with DEP was able to partially prevent the contractile dysfunction. The basal media from lung epithelial cells treated with PM contained several inflammatory cytokines, and we found that monocyte chemotactic protein-1 was a key trigger for cardiomyocyte dysfunction. These results indicate the presence of both direct and indirect effects of PM on cardiomyocyte function in vitro. Future work will focus on elucidating the mechanisms involved in these separate pathways using in vivo models of air pollution exposure.

Cardiovascular dysfunction as a result of tumor burden is becoming a recognized complication; however, the mechanisms remain unknown. A murine model of cancer cachexia has shown marked increases of matrix metalloproteinases (MMPs), known mediators of cardiac remodeling, in the left ventricle. The extent to which MMPs were involved in remodeling remained obscured. To this end a common antibiotic, minocycline, with MMP inhibitory properties was used to elucidate MMP involvement in tumor induced cardiovascular dysfunction. Tumor-bearing mice showed decreased cardiac function with reduced posterior wall thickness (PWTs) during systole, increased MMP and collagen expression consistent with fibrotic remodeling. Administration of minocycline preserved cardiac function in tumor bearing mice and decreased collagen RNA expression in the left ventricle. MMP protein levels were unaffected by minocycline administration, with the exception of MMP-9, indicating minocycline inhibition mechanisms are directly affecting MMP activity. Cancer induced cardiovascular dysfunction is an increasing concern, novel therapeutics are needed to prevent cardiac complications. Minocycline is a well-known antibiotic and recently has been shown to possess MMP inhibitory properties. Our findings presented here show that minocycline could represent a novel use for a long established drug in the prevention and treatment of cancer induced cardiovascular dysfunction.

Pathologic and physiologic factors acting on the heart can produce consistent pressure changes, volume overload, or increased cardiac output. These changes may then lead to cardiac remodeling, ultimately resulting in cardiac hypertrophy. Exercise can also induce hypertrophy, primarily physiologic in nature. To determine the mechanisms responsible for each type of remodeling, it is important to examine the heart at the functional unit, the cardiomyocyte. Tests of individual cardiomyocyte function in vitro provide deeper understanding of the changes occurring within the heart during hypertrophy. Examination of cardiomyocyte function during exercise primarily follows one of two pathways: the addition of hypertrophic inducing agents in vitro to normal cardiomyocytes, or the use of trained animal models and isolating cells following the development of hypertrophy in vivo. Due to the short lifespan of adult cardiomyocytes, a proportionately scant amount of research exists involving the direct stimulation of cells in vitro to induce hypertrophy. These attempts provide the only current evidence, as it is difficult to gather extensive data demonstrating cell growth as a result of in vitro physical stimulation. Researchers have created ways to combine skeletal myocytes with cardiomyocytes to produce functional muscle cells used to repair pathologic heart tissue, but continue to struggle with the short lifespan of these cells. While there have been promising findings regarding the mechanisms that surround cardiac hypertrophy in vitro, the translation of in vitro findings to in vivo function is not consistent. Therefore, the focus of this review is to highlight recent studies that have investigated the effect of exercise on the heart, both in vitro and in vivo.