Unraveling the “Smoker's Paradox” - an In-vitro Study

Objectives: Various clinical studies have reported a better outcome of smokers after myocardial infarction compared with non-smokers. The data are controversial, as some clinical studies did not observe this effect. The cell biological processes involved, which might actually account for the 'Smoker's Paradox', have not been investigated yet. Therefore, the aim of this in-vitro study was to elucidate the effect of cigarette smoke on the viability of cardiomyocytes in the context of hypoxia and reperfusion.

Methods: HL-1 cells were incubated with different concentrations (2%, 4%, 8%, 16%) of cigarette smoke extract (CSE). Using flow-cytometry-based analyses and an LDH-assay the type of cell death induced was analyzed. Western blotting, immunofluorescence staining, an ATP availability assay as well as flow cytometry were further used to identify involved mechanisms in CSE induced HL-1 cell death.

Results: Incubation with CSE led to a concentration-dependent reduction in HL-1 viability. Adding hypoxia enhanced cell death. Flow-cytometry-based analyses showed caspase-independent apoptosis as predominately observed type of cell death partly induced by P53 and apoptosis-inducing factor. Yet a significant increase in LDH release in cardiomyocytes incubated with 4%, 8% and 16% CSE suggests necrosis with rapid DNA depletion. Interestingly, under hypoxic conditions a decreased LDH release under lower CSE concentrations was observed. Moreover, a concentration-dependent increase in proliferation and increased ATP availability under hypoxic conditions was shown.

Conclusion: These results suggest an involvement of both - apoptosis and necrosis in CSE induced cell death. The observed trend for less LDH release in hypoxia after low-level CSE incubation might represent a switch from necrosis to apoptosis, which in combination with the increase in proliferation and ATP availability might account for the 'Smoker's Paradox' and would explain inconsistent results in clinical studies. The retrieved data showed strong evidence for the crucial relevance of the amount of cigarettes smoked. Hence, we are in need of future clinical studies distinguishing between different types of smokers to finally verify or falsify the 'Smoker's Paradox'.

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