Takotsubo Syndrome and Air Pollution: the "Tako-Air" Study

Background

Takotsubo syndrome (TTS) is an acute and reversible form of myocardial injury characterized by typical regional wall motion abnormalities in the absence of culprit epicardial coronary artery disease frequently precipitated by significant emotional stress or serious physical illness. The clinical presentation is usually similar to acute myocardial infarction (MI), with chest pain and/or dyspnea, ST-segment elevation or depression and/or T-wave inversion on the resting electrocardiogram (ECG) and elevation of serum cardiac troponin. Although previously considered a benign disease, it is now clear that TTS is associated with severe acute complications during the acute phase including hemodynamic and electrical instability and up to 5% of in-hospital mortality.

Notably, despite substantial research, the risk factors and pathophysiological mechanisms of TTS are not completely understood, with several hypotheses proposed but none offering a comprehensive explanation. Catecholamine-induced myocardial injury is likely to play a central role, as an emotionally or physically triggering event precipitating the syndrome can be identified in most cases and TTS has been associated with conditions of catecholamine excess (e.g.: pheochromocytoma, central nervous system disorders) and activated specific cerebral regions. Similarly, a markedly reduced parasympathetic activity has been reported during the acute phase of TTS. Moreover, recent studies reported abnormalities in both the functional structure and activity in the areas of the brain related to both emotions and the sympathetic nervous system including the basal ganglia, the hippocampus, the amygdala, and the insula, supporting the role of limbic system dysfunction as a potential mechanism in patients with TTS. Furthermore, it has been proposed that the impaired cardiac function could be the result of an acute coronary microvascular dysfunction with impaired microvascular perfusion leading to a demand-supply mismatch and an ischemic stunning. Therefore, the risk factors for endothelial dysfunction would predispose to the occurrence of TTS.

Air pollution is a complex mixture of unwanted particulate and gaseous material released into the environment by human activities and the world's fourth leading cause of disease and death. Of interest, accumulating evidence supports a consistent relationship between increased exposure to air pollution and CV diseases such as MI and heart failure. Urban ambient air pollution, in particular combustion-derived PM, has received the greatest scientific attention due to the high density of urban populations and increasing levels of traffic-derived emissions and urbanization of societies worldwide. PM includes both organic and inorganic particles (e.g.: dust, pollen, soot, smoke, liquid droplets) and is categorized according to the aerodynamic diameter into coarse particles (2.5-10 μm in diameter; PM10), fine particles (<2.5 μm in diameter; PM2.5), and ultrafine particles (<0.1 μm in diameter; PM0.1). The smallest particles, such as PM2.5 and PM0.1, may contribute disproportionately to the CV toxic effects due to their large reactive surface area and their ability to penetrate deeply into the alveoli and potentially directly into the bloodstream, causing damage and dysfunction of various tissues and cells far from the lung. Gaseous pollutants, in particular nitric dioxide (NO2), ozone (O3), carbon monoxide (CO) and sulphur dioxide (SO2), have been linked to increased morbidity and mortality from CV diseases, likely in an additive manner to PM2.5, but data are still scarce and frequently inconsistent. Mechanistically, the pathogenetic mechanism of air pollution toxicity on the CV system includes oxidative stress, systemic and vascular inflammation, endothelial dysfunction, autonomic and neuroendocrine disruption, metabolic alterations, transcriptional and epigenetic reprogramming. Furthermore, the acute responses to short-term (hours) air pollution exposure include sympathoadrenal activation, release of circulating inflammatory biomarkers, alterations of endothelial function, and acute vascular modifications, such as arterial vasoconstriction and impaired vascular reactivity. The acute effects of air pollution are even more significant in the context of chronic long-term (years) exposure. Indeed, chronic air pollution exposure, by promoting the development of a vulnerable systemic state, can exponentially increase the risk of acute CV events that are likely to be precipitated by acute variations in air pollution exposure. Notably, the investigators recently demonstrated that the exposure to higher concentrations of air pollutants (especially PM2.5) is associated with the presence of vulnerable plaque features and with plaque rupture as a mechanism of coronary instability assessed by optical coherence tomography (OCT) and, moreover, with an enhanced systemic and plaque inflammatory activation. In addition, the investigators also demonstrated that a higher exposure to PM2.5 and PM10 in patients with myocardial ischemia and non-obstructive coronary artery disease is associated with coronary vasomotor abnormalities, and PM2.5 is an independent risk factor for the occurrence of epicardial spasm and MINOCA as clinical presentation.

Of interest, even though the pathogenetic mechanism of air pollution are likely to predispose to the occurrence as well as to mediate a worse clinical presentation and outcome of TTS, the relationship between air pollution and the risk of TTS as well as its clinical course has never been assessed. Furthermore, given the poor understanding of the underlying pathophysiology, there is a lack of evidence-based prevention strategies as well as interventions to reduce the incidence as well as the acute complications of TTS.