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Carbon Monoxide Pollution Promotes Cardiac Remodeling and Ventricular Arrhythmia in Healthy Rats

¹ INSERM, U-637 and ³ INSERM ERI25, Université Montpellier1, Université Montpellier2, Montpellier; ² EA-4278, Université Avignon et des Pays de Vaucluse, UFR Sciences, Avignon; and ⁴ UMR5525, Laboratoire TIMC-PRETA, Université de Grenoble, La Tronche, France

Correspondence and requests for reprints should be addressed to Sylvain Richard, Ph.D., INSERM U-637 Physiopathologie Cardiovasculaire, CHU Arnaud de Villeneuve, F-34295 Montpellier, France. E-mail: sylvain.richard{at}inserm.fr

Rationale: Epidemiologic studies associate atmospheric carbon monoxide (CO) pollution with adverse cardiovascular outcomes and increased cardiac mortality risk. However, there is a lack of data regarding cellular mechanisms in healthy individuals.

Objectives: To investigate the chronic effects of environmentally relevant CO levels on cardiac function in a well-standardized healthy animal model.

Methods : Wistar rats were exposed for 4 weeks to filtered air (CO < 1 ppm) or air enriched with CO (30 ppm with five peaks of 100 ppm per 24-h period), consistent with urban pollution. Myocardial function was assessed by echocardiography and analysis of surface ECG and in vitro by measuring the excitation-contraction coupling of single left ventricular cardiomyocytes.

Measurements and Main Results: Chronic CO pollution promoted left ventricular interstitial and perivascular fibrosis, with no change in cardiomyocyte size, and had weak, yet significant, effects on in vivo cardiac function. However, both contraction and relaxation of single cardiomyocytes were markedly altered. Several changes occurred, including decreased Ca²⁺ transient amplitude and Ca²⁺ sensitivity of myofilaments and increased diastolic intracellular Ca²⁺ subsequent to decreased SERCA-2a expression and impaired Ca²⁺ reuptake. CO pollution increased the number of arrhythmic events. Hyperphosphorylation of Ca²⁺-handling and sarcomeric proteins, and reduced responses to β-adrenergic challenge were obtained, suggestive of moderate CO-induced hyperadrenergic state.

Conclusions: Chronic CO exposure promotes a pathological phenotype of cardiomyocytes in the absence of underlying cardiomyopathy. The less severe phenotype in vivo suggests a role for compensatory mechanisms. Arrhythmia propensity may derive from intracellular Ca²⁺ overload.

Key Words: heart failure • atmospheric pollution • Ca²⁺ handling • protein kinase A pathway

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Most studies of the effects of atmospheric pollution provide correlations between air quality and cardiovascular outcomes, but do not provide mechanistic information owing to technical limitations in human subjects. Our findings provide a rationale at the cellular and molecular levels in support of epidemiologic studies pointing to the deleterious effects of carbon monoxide pollution on cardiac function. What This Study Adds to the Field This study shows that the deleterious effects of chronic carbon monoxide exposure may be barely detectable. However, even in the absence of underlying cardiopathy, cardiomyocytes may develop a pathological phenotype with some features commonly observed at the early stages of heart failure.