Citations

Tamoxifen is biotransformed by CYP2D6 to 4‐hydroxytamoxifen and 4‐hydroxy N‐desmethyl tamoxifen (endoxifen), both with greater antiestrogenic potency than the parent drug. Patients with certain CYP2D6 genetic polymorphisms and patients who receive strong CYP2D6 inhibitors exhibit lower endoxifen concentrations and a higher risk of disease recurrence in some studies of tamoxifen adjuvant therapy of early breast cancer. We summarize evidence from the literature and provide therapeutic recommendations for tamoxifen based on CYP2D6 genotype.

Bioprostheses are prone to structural valve degeneration, resulting in limited long-term durability. A significant challenge when comparing the durability of different types of bioprostheses is the lack of a standardized terminology for the definition of a degenerated valve. This issue becomes especially important when we try to compare the degeneration rate of surgically inserted and transcatheter bioprosthetic valves. This document, by the VIVID (Valve-in-Valve International Data), proposes practical and standardized definitions of valve degeneration and provides recommendations for the timing of clinical and imaging follow-up assessments accordingly. Its goal is to improve the quality of research and clinical care for patients with deteriorated bioprostheses by providing objective and strict criteria that can be utilized in future clinical trials. We hope that the adoption of these criteria by both the cardiological and surgical communities will lead to improved comparability and interpretation of durability analyses.

There is a mediolateral gradient in activation of the parasternal intercostal (PI) muscle during inspiration. In the present study, we tested the hypotheses that serotonergic [5-hydroxytryptamine (5-HT)] input from descending central drive and/or intrinsic size-related properties of PI motoneurons leads to the differential activation of PI muscles. In dogs, PI motoneurons innervating the medial and lateral regions of the PI muscles at the T3–T5interspaces were retrogradely labeled by intramuscular injection of cholera toxin B subunit. After a 10-day survival period, PI motoneurons and 5-HT terminals were visualized by using immunohistochemistry and confocal imaging. There were no differences in motoneuron morphology among motoneurons innervating the medial and lateral regions of the PI muscle. However, the number of 5-HT terminals and the 5-HT terminal density (normalized for surface area) were greater in motoneurons innervating the medial region of the PI muscle compared with the lateral region. These results suggest that differences in distribution of 5-HT input may contribute to regional differences in PI muscle activation during inspiration and that differences in PI motoneuron recruitment do not relate to size.

The relative contributions of a central neural oscillator and of the delay in α-adrenergic transmission within the baroreflex loop in the predominance of low-frequency (LF) cardiovascular variability during sympathetic activation in humans are unclear. We measured R-R interval (RR), muscle sympathetic nerve activity (MSNA), blood pressure (BP), and their variability in 10 normal subjects during sympathetic activation achieved by BP lowering with sodium nitroprusside (SNP) and α-adrenergic blockade using phentolamine. SNP and phentolamine induced comparable reductions in BP ( P > 0.25). Despite tachycardia and sympathetic activation with both SNP and phentolamine, LF variability in RR, MSNA, and BP increased during SNP and decreased during phentolamine (SNP: RR +20 ± 6%, MSNA +3 ± 5%, systolic BP +9 ± 6%, diastolic BP +7 ± 5%; phentolamine: RR −2 ± 7%, MSNA −34 ± 6%, systolic BP −16 ± 8%, diastolic BP −13 ± 4%, P< 0.05 except systolic BP, where P = 0.09). Thus LF variability is reduced when sympathetic activation is induced by α-adrenergic blockade. This suggests that α-adrenergic transmission within the baroreflex loop may contribute importantly to the predominance of LF cardiovascular variability associated with sympathetic excitation in humans.

Chemoreflex stimulation elicits both hyperventilation and sympathetic activation, each of which may have different influences on oscillatory characteristics of cardiovascular variability. We examined the influence of hyperventilation on the interactions between changes in R-R interval (RR) and muscle sympathetic nerve activity (MSNA) and changes in neurocirculatory variability, in 14 healthy subjects. We performed spectral analysis of RR and MSNA variability during each of the following interventions: 1) controlled breathing, 2) maximal end-expiratory apnea, 3) isocapnic voluntary hyperventilation, and 4) hypercapnia-induced hyperventilation. MSNA increased from 100% during controlled breathing to 170 ± 25% during apnea ( P = 0.02). RR was unchanged, but normalized low-frequency (LF) variability of both RR and MSNA increased markedly ( P < 0.001). During isocapnic hyperventilation, minute ventilation increased to 20.2 ± 1.4 l/min ( P < 0.0001). During hypercapnic hyperventilation, minute ventilation also increased (to 19.7 ± 1.7 l/min) as did end-tidal CO2 (both P < 0.0001). MSNA remained unchanged during isocapnic hyperventilation (104 ± 7%) but increased to 241 ± 49% during hypercapnic hyperventilation ( P < 0.01). RR decreased during both isocapnic and hypercapnic hyperventilation ( P < 0.05). However, normalized LF variability of RR and of MSNA decreased ( P < 0.05) during both isocapnic and hypercapnic hyperventilation, despite the tachycardia and heightened sympathetic nerve traffic. In conclusion, marked respiratory oscillations in autonomic drive induced by hyperventilation may induce dissociation between RR, MSNA, and neurocirculatory variability, perhaps by suppressing central genesis and/or inhibiting transmission of LF cardiovascular rhythms.