Right heart function in impaired left ventricular diastolic function: 2D speckle tracking echocardiography–based and Doppler tissue imaging–based analysis of right atrial and ventricular function

Aim

The aim of our study was to describe right atrial (RA) and right ventricular (RV) function, assessed by Doppler tissue imaging and 2D speckle tracking echocardiography (2DSTE), in women with signs of early impaired left ventricular diastolic function (DD).

Methods and Results

In a cross‐sectional trial, standard parameters of diastolic and right heart function were investigated in 438 women of the Berlin Female Risk Evaluation (BEFRI) study. In a subset of women, average peak systolic RA strain (RAS), as well as the average peak systolic RV strain of the free wall (RVS free wall) and of all RV segments (average RV strain; RVS Avg), was analyzed using 2DSTE. Compared to women with normal diastolic function (DD0), RAS, RVS free wall and RVS Avg were significantly reduced in DD (43.1% ± 11.9%, ?26.7% ± 5.6%, and ?23.3% ± 3.5% in DD0; vs 35.1% ± 10.4%, ?23.9% ± 5.5%, and ?20.6% ± 3.8% in DD; P < .01). Peak RV myocardial velocity (RV‐IVV) and acceleration during isovolumetric contraction (RV‐IVA) were markedly higher in DD (15.0 ± 3.9 cm/s and 3.1 ± 1.0 m/s² in DD vs 11.9 ± 3.2 cm/s and 2.8 ± 0.8 m/s² in DD0; P < .05). RAS and RV‐IVV were significantly associated with DD after adjustment to age, BMI, and left atrial strain in multivariate regression analysis.

Conclusion

Systolic right heart function is significantly altered in DD. DTI as well as 2DSTE constitute sensitive echocardiographic tools that enable the diagnosis of impaired right heart mechanics in early‐staged DD.     

Control of APC/C-dependent ubiquitin chain elongation by reversible phosphorylation

Most metazoan E3 ligases contain a signature RING domain that promotes the transfer of ubiquitin from the active site of E2 conjugating enzymes to lysine residues in substrates. Although these RING-E3s depend on E2 enzymes for catalysis, how they turn on their E2s at the right time and place remains poorly understood. Here we report a phosphorylation-dependent mechanism that ensures timely activation of the E2 Ube2S by its RING-E3, the anaphase-promoting complex (APC/C); while phosphorylation of a specific serine residue in the APC/C coactivator Cdc20 prevents delivery of Ube2S to the APC/C, removal of this mark by PP2A^B56 allows Ube2S to bind the APC/C and catalyze ubiquitin chain elongation. PP2A^B56 also stabilizes kinetochore–microtubule attachments to shut off the spindle checkpoint, suggesting that cells regulate the E2–E3 interplay to coordinate ubiquitination with critical events during cell division.By promoting the ubiquitination and proteasomal degradation of anaphase inhibitors, the anaphase-promoting complex (APC/C) triggers sister chromatid separation and mitotic exit (1–5). The APC/C also targets kinases and microtubule-binding proteins that ensure accurate assembly of the mitotic spindle. Misregulation of the APC/C has dramatic consequences for cell cycle control; whereas APC/C inhibition causes mitotic arrest and cell death, its untimely activation results in aneuploidy, a common feature of human cancer cells (6).As a RING-dependent E3 ligase, the APC/C stimulates the transfer of ubiquitin from the catalytic cysteine of E2 conjugating enzymes to lysine residues in substrates. In most cases, the APC/C initiates chain formation by using a specific E2, Ube2C (7–10). Once the first ubiquitin molecules have been attached to substrates, another conserved E2, Ube2S, extends K11-linked chains that are recognized by the proteasome for degradation (11–16). Ube2S frequently acts on short chains rather than on single ubiquitin subunits, thereby producing branched conjugates that impart high affinity for proteasomal receptors (13). Consistent with an important role in cell division, activation of Ube2S during mitosis results in a dramatic increase in the abundance of K11 linkages (17, 18), a chain topology required for APC/C-dependent substrate degradation (19).As with many key cell cycle regulators, the APC/C and Ube2S need to be under tight control, and overexpression of Ube2S can promote tumor growth and metastasis in mice (20). The correct timing of APC/C activation is ensured by the spindle checkpoint, a signaling cascade turned on by kinetochores that have not achieved bipolar attachment to the spindle (4, 21, 22). Spindle checkpoint signaling leads to formation of the mitotic checkpoint complex (MCC), composed of Mad2, BubR1, Bub3, and Cdc20. When bound to the APC/C, the MCC competes for recognition of substrate KEN boxes and puts the APC/C coactivator Cdc20 in a position where it is unable to engage another degron, the D box (23–25). In contrast, the MCC does not occupy the binding sites for APC/C E2s or impede the ability of the APC/C to stimulate ubiquitin transfer by Ube2S (12). Thus, although overexpression of Ube2S has been associated with tumorigenesis, the mechanisms that restrict its activity during mitosis have remained elusive.RING-E3s, such as the APC/C, engage their E2 enzymes in a dynamic manner (26). On binding a charged E2, the RING domain stabilizes a closed conformation between the E2 and its donor ubiquitin (14, 27–30). Once this ubiquitin is transferred to a target lysine, the E2 dissociates from the RING domain to allow for its recharging by the E1 (31). For most RING-E3s, the cycles of E2 engagement and dissociation are thought to occur constitutively (32), and only a few examples of controlled E2 activation are known. Access of Cdc34 to its specific RING-E3, the Skp1-Cul1-F box (SCF) complex, can be regulated by phosphorylation or competition with the inhibitory protein glomulin (33, 34). Reminiscent of this situation, Ube2S interacts with the APC/C in a cell cycle-dependent manner, and depletion of Cdc20 prevents Ube2S from stably binding to the APC/C in cells (12, 15). However, as part of the MCC, Cdc20 already associates with the APC/C during prometaphase, when APC/C activity must be low to allow sufficient time for chromosome alignment. How the ability of Ube2S to build ubiquitin chains is restricted during early stages of mitosis to safeguard cells against premature APC/C activation remains unknown.In this study, we identified a mechanism that establishes how the RING-E3 APC/C activates Ube2S at the right time and place. In early mitosis, phosphorylation of a specific serine residue in the APC/C coactivator Cdc20 prevents the stable association of Ube2S with Cdc20 and the APC/C. Conversely, removal of the inhibitory mark on Cdc20 by the phosphatase PP2A^B56 allows Ube2S to engage the APC/C and catalyze ubiquitin chain elongation. PP2A^B56 also stabilizes the kinetochore–microtubule interface to silence the spindle checkpoint (35, 36), suggesting that cells regulate the interplay between RING-E3s and their E2s to coordinate ubiquitination with important events in cell division.     

Coronary cardiac allograft vasculopathy versus native atherosclerosis: difficulties in classification

Cardiac allograft vasculopathy is regarded as a progressive and diffuse intimal hyperplastic lesion of arteries and veins that leads to insidious vessel narrowing and to allograft ischemic disease, such as acute myocardial infarction or sudden cardiac death. The coronary lesions in transplanted hearts are considered as a particular type of arteriosclerosis with many similarities but also significant differences compared to native coronary atherosclerosis. It is particularly difficult for pathologists to systematically classify the lesions and to elucidate their origins, since over time, the allograft immune responses cause vascular pathology characterized by not only the onset of de novo fibrocellular lesions but also remodeling of already-existing native atherosclerotic lesions in the donor heart. Intraplaque hemorrhages, which result from newly formed leaky microvessels, may cause rapid increase of stenosis and generate a substrate for plaque destabilization. Comparing cardiac allograft vasculopathy from explanted hearts at autopsy with native coronary atherosclerosis from hearts removed at transplantation has revealed that ongoing intraplaque hemorrhages are also an important feature of cardiac allograft vasculopathy and may be important factors in the rapid progression of cardiac allograft vasculopathy.     

Personal Preferences Regarding Family Member Presence during Resuscitation

OBJECTIVES: Previous studies have shown that family members wish to be present during the resuscitation of a family member. No studies have addressed whether the patient would want family members present if he or she required resuscitation. The authors wanted to determine patients' preferences regarding family member presence during their own resuscitation. METHODS: A seven-item survey was administered to a sample of patients and their family members older than 17 years of age on six randomly chosen shifts in an academic community hospital emergency department. Responses were analyzed using chi-square and t-tests. Subjective comments were also recorded. RESULTS: A total of 266 subjects were asked to participate in the study; 200 subjects agreed to complete the survey. Most (72%) wanted a family member present. However, 21% did not wish any family member to be present. Positive responders (family present) tended to be younger (mean, 39.4 years; 95% confidence interval = 36.7 to 42.2) than negative responders (mean, 50.5 years; 95% confidence interval = 42.9 to 55.7; p < 0.001). Positive responders were also more likely to be nonwhite (chi2 = 6.29, p < 0.05). Gender, education, or health status was not associated with responder type. Of positive responders, 56% stated they wanted only certain members present, and these preferences were variable. CONCLUSIONS: Patients preferred to have family members present during their resuscitation. However, most of the positive responders wanted only certain members present, and approximately one in five patients, who tended to be older and white, did not want any family present. This study does not support an open policy of allowing family members into a resuscitation without prior knowledge of the patient's preferences.     

Caring for the caregivers: Innovative program for oncology nurses.

An innovative program, Care for the Professional Caregiver, was designed to provide staff nurses in a cancer program with the opportunity to learn about coping with stress in their practice. The program was evaluated using quantitative and qualitative methods. The findings clearly describe the benefits of the program on both a short- and long-term basis. The value of connecting with other cancer nurses, supporting each other, and sharing stories about their work life experiences resulted in benefits to the nurse as an individual, as a team member, and as a professional practitioner. The program achieved its aims and is recommended for ongoing implementation.