BackgroundBioprosthetic aortic valve degeneration is increasingly common, often unheralded, and can have catastrophic consequences.ObjectivesThe authors sought to assess whether 18F-fluoride positron emission tomography (PET)-computed tomography (CT) can detect bioprosthetic aortic valve degeneration and predict valve dysfunction.MethodsExplanted degenerate bioprosthetic valves were examined ex vivo. Patients with bioprosthetic aortic valves were recruited into 2 cohorts with and without prosthetic valve dysfunction and underwent in vivo contrast-enhanced CT angiography, 18F-fluoride PET, and serial echocardiography during 2 years of follow-up.ResultsAll ex vivo, degenerate bioprosthetic valves displayed 18F-fluoride PET uptake that colocalized with tissue degeneration on histology. In 71 patients without known bioprosthesis dysfunction, 14 had abnormal leaflet pathology on CT, and 24 demonstrated 18F-fluoride PET uptake (target-to-background ratio 1.55 [interquartile range (IQR): 1.44 to 1.88]). Patients with increased 18F-fluoride uptake exhibited more rapid deterioration in valve function compared with those without (annualized change in peak transvalvular velocity 0.30 [IQR: 0.13 to 0.61] vs. 0.01 [IQR: −0.05 to 0.16] ms−1/year; p < 0.001). Indeed 18F-fluoride uptake correlated with deterioration in all the conventional echocardiographic measures of valve function assessed (e.g., change in peak velocity, r = 0.72; p < 0.001). Each of the 10 patients who developed new overt bioprosthesis dysfunction during follow-up had evidence of 18F-fluoride uptake at baseline (target-to-background ratio 1.89 [IQR: 1.46 to 2.59]). On multivariable analysis, 18F-fluoride uptake was the only independent predictor of future bioprosthetic dysfunction.Conclusions18F-fluoride PET-CT identifies subclinical bioprosthetic valve degeneration, providing powerful prediction of subsequent valvular dysfunction and highlighting patients at risk of valve failure. This technique holds major promise in the diagnosis of valvular degeneration and the surveillance of patients with bioprosthetic valves. (18F-Fluoride Assessment of Aortic Bioprosthesis Durability and Outcome [18F-FAABULOUS]; NCT02304276)

Background-The ␣ 1 -adrenoceptor-blocking antihypertensive doxazosin has been associated with increased risk of heart failure and is known to induce prostate cell apoptosis. We hypothesized that it might also induce apoptosis in cardiomyocytes. Methods and Results-Hoechst dye vital staining and flow cytometry provided evidence that doxazosin induced apoptosis time-and dose-dependently in cardiomyocytes of the HL-1 cell line. TUNEL assays and 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) viability test confirmed that doxazosin induced DNA damage and cell death in these cells. MTT tests showed that doxazosin treatment decreased cell viability in primary cultures of neonatal rat cardiomyocytes, and Hoechst dye vital staining demonstrated doxazosin-induced apoptosis in primary cultures of human adult cardiomyocytes. The proapoptotic effect of doxazosin on cardiomyocytes seems not to depend on ␣ 1 blockade, because it was not modified by cotreatment with ␣-or ␤-adrenergic agonists or with the irreversible ␣ 1 -blocker phenoxybenzamine and because doxazosin also decreased the viability of NIH 3T3 cells, which lack ␣ 1 -adrenoceptors. It also does not involve calcineurin, being unaffected by the presence of the calcineurin inhibitors cyclosporin A and FK506. Three other ␣ 1 -blockers were also investigated; prazosin was proapoptotic, like doxazosin, but 5-methylurapidil and terazosin were not. Conclusions-The ␣ 1 -blockers doxazosin and prazosin induce the apoptosis of cardiomyocytes cultured in vitro by a mechanism that is independent of ␣ 1 blockade and calcineurin.

Hybrids. -The coumarin-resveratrol hybrid (IV) is accessible either by a Pechmann procedure [cf. (I)+(II)→(III)] or by a Perkin reaction. The latter allows also the synthesis of analogue (VIII). The new molecules show remarkable vasorelaxant effects and significant human platelet antiaggregatory activity. They reveal a pharmacological profile similar or even better compared to that of t-RESV. -(VILAR*, S.; QUEZADA, E.; SANTANA, L.; URIARTE, E.; YANEZ, M.; FRAIZ, N.; ALCAIDE, C.; CANO, E.; ORALLO, F.; Bioorg. Med. Chem. Lett. 16 (2006) 2, 257-261; Dep. Quim. Org., Fac. Farm.

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