Acetaldehyde within e‐cigarette aerosol and cigarette smoke triggers intracellular calcium release in primary adult cardiomyocytes that is exacerbated in ALDH2*2 mice

Abstract

Background Cigarette smoke can trigger calcium influx in cardiac myocytes that over time can lead to cardiovascular diseases linked to calcium handling such as atrial fibrillation and heart failure. E-cigarette vapor, similar to cigarette smoke, contains aldehydes that trigger intracellular calcium in neurons. Further, ~560 million people carry an inactivating genetic variant in aldehyde dehydrogenase 2 (ALDH2), known as ALDH2*2, the primary enzyme responsible for metabolizing acetaldehyde. However, little is known how acetaldehyde present in cigarette smoke and e-cigarette aerosol, when coupled with genetics, influence intracellular calcium release within the cardiac myocyte. Hypothesis: Acetaldehyde in e-cigarette aerosol and cigarette smoke can trigger calcium influx in cardiac myocytes. Methods: ALDH2 expression and activity were quantified from wild type ALDH2 and ALDH2*2 male mice heart homogenates. Further, ALDH2 and ALDH2*2 primary adult cardiac myocytes were treated with a short burst of acetaldehyde (0.1-100 μM for 30 seconds, to recapitulate vaping or smoking) and intracellular calcium levels were assessed by fura-2 (5 μM). A Student's t-test was used to compare responses between rodents with significance *p<0.05. Results: The enzymatic activity to metabolize aldehydes within the heart was 3-fold lower for the ALDH2*2 relative to ALDH2 heart homogenates (0.14±0.003* versus 0.45±0.02, ALDH2/GAPDH relative densitometry units, n=3/group). Further, acetaldehyde (0.1 μM) triggered intracellular calcium influx that was 5-fold higher for ALDH2*2 myocytes compared to ALDH2 myocytes (8.32±0.72 %* versus 1.46±0.31%, percent of maximal response, n=4-6 cells from 4 biological replicates). Peak intracellular calcium influx was also ~40% higher for ALDH2*2 myocytes when compared to wild type ALDH2 myocytes over a range of additional acetaldehyde doses (0.1-100 μM) tested. Conclusion: Acetaldehyde, the primary aldehyde in e-cigarette aerosol, triggers intracellular calcium influx that is ~40% greater for rodents carrying an inactivating ALDH2 variant, ALDH2*2. People carrying an inactive ALDH2*2 genetic variant may be more susceptible to acetaldehyde present within e-cigarette vapor and cigarette smoke which over time and continued use lead to developing cardiovascular diseases linked to altered calcium handling.