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This study evaluated the gender related long-term prognostic value of adenosine perfusion and dobutamine wall motion imaging as assessed during a combined single-session stress cardiac magnetic resonance (CMR) examination. In 717 patients a combined CMR stress examination was performed. Inducible perfusion deficits and wall motion abnormalities were identified visually. Clinical parameters were assessed at the time of the CMR examination. All patients were contacted to determine the occurrence of hard cardiac events (cardiac death, myocardial infarction) during a median follow-up period of 5.3 years. A complete combined CMR examination and follow-up data were available in 679 patients (471 men). A total of 77 hard cardiac events (63 in men) occurred during follow-up. Multivariate analysis revealed the presence of inducible perfusion deficits or wall motion abnormalities as independent predictors of hard cardiac events for both gender with an incremental value over conventional cardiovascular risk factors. In case of a negative stress test result, event-free survival was 100% in women for 4 years and >99% in men for 2 years after the CMR examination. CMR perfusion and wall motion testing are equally suited for cardiac risk stratification in men and women. Stress CMR negative women exhibited very low event rates up to 4 years following the examination, while in men annual event rates increased after the second year. Consequently, the generally proposed 2-year warranty period of non-invasive stress testing may be prolonged to a 4 year level in CMR stress testing negative women.

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Integrins link the cytoskeleton to the extracellular matrix, providing outside-in/inside-out signalling essential for vascular smooth muscle cell (VSMC) migration in atherosclerosis. The integrin av subunit is synthesised from its precursor via furin-dependent endoproteolytic cleavage. Furin is a proprotein convertase (PC) highly expressed in VSMCs and in human atherosclerotic lesions. Inhibition of av processing inhibits binding to vitronectin and migration. However, the precise role of furin-dependent av cleavage on integrin bidirectional signalling and subsequent VSMC functions is unknown. Our present study demonstrates that the furin-like PC inhibitor decanoyl-RVKR-chloromethylketone (dec-CMK) inhibited av cleavage. This reduced vitronectin-induced (outside-in) focal adhesion kinase (FAK)- and paxillin-phosphorylation, and VSMC motility. Inside-out-stimulated, integrin- mediated VSMC adhesion/migration relied on integrin-adaptor protein activation following protein kinase C (PKC) and ERK1/2 phosphorylation. In contrast to outside-in signalling, PKC-dependent phosphorylation of FAK and paxillin was unaffected by the status of integrin cleavage. Still, cytoskeleton and focal adhesion site rearrangements were modulated by the inhibition of furin-dependent integrin cleavage, thereby lessening inside-out dependent migration. Hence, we find that integrin bidirectional signalling is critically controlled by furin. Furin- dependent integrin processing modulates rapid adaptive integrin/cytoskeleton changes, essential to VSMC motility, which represents a crucial component in atherosclerosis and restenosis.

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