Despite advancements in symptom management for heart failure (HF), this devastating clinical syndrome remains the leading cause of death in the developed world. Studies using animal models have greatly advanced our understanding of the molecular mechanisms underlying HF; however, differences in cardiac physiology and the manifestation of HF between animals, particularly rodents, and humans necessitates the direct interrogation of human heart tissue samples. Nevertheless, an ever-present concern when examining human heart tissue samples is the potential for artefactual changes related to temperature changes during tissue shipment or sample processing. Herein, we examined the effects of temperature on the post-translational modifications (PTMs) of sarcomeric proteins, the proteins responsible for muscle contraction, under conditions mimicking those that might occur during tissue shipment or sample processing. Using a powerful top-down proteomics method, we found that sarcomeric protein PTMs were differentially affected by temperature. Specifically, cardiac troponin I and enigma homolog isoform 2 showed robust increases in phosphorylation when tissue was incubated at either 4 °C or 22 °C. The observed increase is likely due to increased cyclic AMP levels and activation of protein kinase A in the tissue. On the contrary, cardiac troponin T and myosin regulatory light chain phosphorylation decreased when tissue was incubated at 4 °C or 22 °C. Furthermore, significant protein degradation was also observed after incubation at 4 °C or 22 °C. Overall, these results indicate that temperature exerts various effects on sarcomeric protein PTMs and careful tissue handling is critical for studies involving human heart samples. Moreover, these findings highlight the power of top-down proteomics for examining the integrity of cardiac tissue samples.

Background Cytomegalovirus (CMV) infection in kidney transplant recipients has been anecdotally observed with concomitant or subsequent opportunistic infections (OI), but this association has yet to be defined or quantified. Methods Patients who received a renal transplant between 1/1/2005 and 6/30/2014 and developed CMV infection were matched to controls in a ratio of 1:2 and the rates of opportunistic co‐infection were calculated within pre‐specified time frames (−30 days to +90 days and −30 days to +180 days). The primary outcome was composite OI rate, and secondary outcomes included time to OI and patient and graft outcomes. CMV‐OI association rates were estimated via conditional logistic regression. Results There were 2405 patients who received a renal transplant during the study period; 394 cases of CMV infection were identified. These cases were matched to 783 controls for a total of 805 participants. OI occurred in 14 patients in the CMV case group (CMV+) and in 5 patients in the control group (CMV‐) in the −30 to +90 day time period (3.55% vs 0.64%, OR = 5.60, 95% CI: 2.02‐12.55). When considering 180‐day follow‐up, OI occurred in 17 CMV+ patients and 8 CMV‐ patients (4.3% vs 1%, OR = 4.25, 95% CI: 1.83‐9.85). Mean time from CMV diagnosis to OI was 33 ± 64 days (median 7 days). Mortality was 3 times more likely in the group with concomitant OI (CMV+/OI+) as compared to a matched cohort of patients with CMV infection without OI (CMV+/OI‐) (unadjusted HR 3.02, 1.64‐5.55, Tables 6 and 7). Cumulative survival for CMV+/OI+ patients was significantly worse than CMV+/OI‐ patients (P < 0.01). Conclusions CMV is associated with a significantly increased risk of co‐infection with OI, particularly fungal infections. Clinical suspicion for concomitant OI should drive further workup after a CMV diagnosis. Future studies are needed to better define those patients at highest risk to elucidate subpopulations where the benefits of prophylaxis outweigh the potential risks associated with these therapies.

Aims: Nondipping blood pressure (BP) is associated with higher risk for hypertension and advanced target organ damage. Insomnia is the most common sleep complaint in the general population. We sought to investigate the association between sleep quality and insomnia and BP nondipping cross-sectionally and longitudinally in a large, community-based sample. Methods: A subset of the Wisconsin Sleep Cohort (n = 502 for cross-sectional analysis and n = 260 for longitudinal analysis) were enrolled in the analysis. Polysomnography measures were used to evaluate sleep quality. Insomnia symptoms were obtained by questionnaire. BP was measured by 24-h ambulatory BP monitoring. Logistic regression models estimated cross-sectional associations of sleep quality and insomnia with BP nondipping. Poisson regression models estimated longitudinal associations between sleep quality and incident nondipping over a mean 7.4 years of follow-up. Systolic and diastolic nondipping were examined separately. Results: In cross-sectional analyses, difficulty falling asleep, longer waking after sleep onset, shorter and longer total sleep time, lower sleep efficiency and lower rapid eye movement stage sleep were associated with higher risk of SBP and DBP nondipping. In longitudinal analyses, the adjusted relative risks (95% confidence interval) of incident systolic nondipping were 2.1 (1.3–3.5) for 1-h longer waking after sleep onset, 2.1 (1.1–5.1) for 7–8 h total sleep time, and 3.7 (1.3–10.7) for at least 8-h total sleep time (compared with total sleep time 6–7 h), and 1.9 (1.1–3.4) for sleep efficiency less than 0.8, respectively. Conclusion: Clinical features of insomnia and poor sleep quality are associated with nondipping BP. Our findings suggested nondipping might be one possible mechanism by which poor sleep quality was associated with worse cardiovascular outcomes.

Background. Fractures are a common and burdensome problem among kidney transplant recipients (KTRs). Proton pump inhibitors (PPIs) are frequently used after kidney transplantation and have been associated with increased fracture risk in the general population. This study aimed to determine whether PPI use is associated with incidence of major fractures in KTRs. Methods. Using the Wisconsin Allograft Recipient Database, we identified 155 KTRs with a major fracture that occurred at least 12 months after transplantation. Controls were selected using incidence-density sampling. Use of PPIs and histamine 2-receptor antagonists (H2RA) during the year before the index date were identified. Results. A total of 155 cases were matched to 685 controls. Within 1 year before the index date, 68% of cases and 52% of controls used a PPI, and 16% of cases and 11% of controls used an H2RA. PPI use was associated with higher incidence of major fractures in unadjusted analysis (odds ratio [OR], 2.4; 95% CI, 1.6-3.5) and in adjusted analyses controlling for demographic and transplant-related covariates and use of corticosteroids, bisphosphonates, vitamin D and calcium supplements (OR, 1.9; 95% CI, 1.2-3.1). H2RA use was not associated with incidence of major fractures in adjusted analyses (OR, 1.0; 95% CI, 0.5-1.8). The associations between PPI use and fractures remained similar in analyses limited to spine and hip fractures. Conclusions. Use of PPIs, but not H2RAs, is associated with a higher risk of major fractures among KTRs. Clinicians should individualize PPI use in KTRs, evaluating the risks and benefits of prescribing and continuing PPIs in KTRs.

The risk of cytomegalovirus infection (CMV) after rejection treatment is poorly understood. To investigate this, we conducted a case/control (1:2) analysis of adult renal transplant recipients between January 1, 2005 and December 31, 2015, via incidence density sampling and survival analysis. Our objective was to evaluate the association of prior acute rejection with subsequent CMV, including epidemiology and outcomes. There were 2481 eligible renal transplants within the study period and 251 distinct CMV infections. Despite the use of antiviral prophylaxis rejection was a significant risk factor for CMV on unadjusted (HR 1.73 [1.34, 2.24] P < 0.05) and adjusted analysis (HR 1.46 [1.06, 2.04] P < 0.05). When matching cases to controls patients with CMV had significantly more rejection prior to CMV diagnosis (26.7% vs 14.2%, P < 0.01). CMV was associated with a twofold increased risk of prior rejection on unadjusted (OR 1.94, 95%CI: 1.28‐2.96, P < 0.01) and adjusted analysis (OR 2.16, 95% CI: 1.31‐3.58, P < 0.01). Patients with rejection preceding CMV had significantly increased graft loss (HR 2.89, 95% CI: 1.65‐5.09, P < 0.01) and mortality (HR 1.82, 95% CI: 1.12‐4.24, P = 0.03) as compared to those CMV cases without rejection. In conclusion, rejection is a risk factor for CMV infection that appears to persist for 1 year. Preceding rejection events increased risk of graft loss and mortality in CMV patients. Given this, prolonged surveillance monitoring for CMV after rejection may be warranted. Studies are needed investigating optimal monitoring strategies.

Background: In the general population, use of proton pump inhibitor (PPI) has been linked to higher risk of osteoporotic fractures. PPI is commonly prescribed in kidney transplant recipients (KTRs). However, the effect of PPI on osteoporosis in KTRs is largely unstudied. Methods: A total of 1,774 adult KTRs in the Wisconsin Allograft Recipient Database with at least one eligible bone mineral density (BMD) measurement at least 3 months after transplantation were included in the analyses. Associations between use of PPI and histamine-2 receptor antagonist (H2RA) at 3 months after transplantation and subsequent slope of T-score were assessed. Results: A total of 1,478 (83.3%) participants were using a PPI at 3 months after transplantation. Compared to the use of H2RA, use of PPI was not significantly associated with annualized slope of hip T-score (β = -0.0039, 95% CI -0.00497 to 0.0021) or annualized slope of spine T-score (β = -0.017, 95% CI -0.049 to 0.083) after adjustment for potential confounders. Similarly, no significant association between use of PPI and slope of T-score was observed when defining PPI/H2RA exposure as use within 6 months of the initial BMD measurement, or only including participants with at least 2 BMD measurements, or stratified by different age and sex. Conclusions: Use of PPI was not associated with an increased rate of BMD loss in KTRs. Our results support previous findings that PPI use does not have a significant effect on bone mineral loss.

Background: Arteriovenous (AV) access dysfunction is a common complication in hemodialysis patients. Markers of vascular calcification are associated with cardiovascular outcomes and mortality in this population, but their association with vascular access outcomes is unknown. In this study, we aimed to evaluate the association between selected vascular calcification makers and vascular access complications in a cohort of hemodialysis patients. Method: Fetuin-A, osteopontin (OPN), osteoprotegerin (OPG), and bone morphogenetic protein-7 (BMP-7) were measured in blood samples from 219 dialysis patients in the Choice for Healthy Outcomes in Caring for end-stage renal disease study; these patients were using a permanent vascular access. Participants were followed for up to 1 year or until the occurrence of a vascular access intervention or replacement. Associations with AV fistula (AVF) and AV graft (AVG) intervention-free survival were assessed in models adjusted for demographic characteristics, comorbidities, and inflammation. Results: A total of 24 out 103 participants with an AVF and 43 out of 116 participants with an AVG had an intervention during follow-up. Lower fetuin-A, higher OPN, and higher BMP-7 were associated with a higher risk of AVF intervention (adjusted hazard ratios [aHR] for highest versus lowest tertile = 0.30 [95% CI 0.10–0.94]) for fetuin-A, 3.84 (95% CI 1.16–12.74) for OPN, and 3.49 (95% CI 1.16–10.52) for BMP-7. OPG was not significantly associated with the risk of AVF intervention. The associations of OPN and BMP-7 with AVF intervention appeared stronger among participants without diabetes (aHR 8.06; 95% CI 1.11–58.57 for OPN and aHR 2.55; 95% CI 1.08–6.08 for BMP-7, respectively) than among their counterparts with diabetes (p interaction = 0.06). None of the markers studied were significantly associated with AVG interventions. Conclusion: Lower fetuin-A and higher OPN and BMP-7 are associated with complications in AVF but not in AVG, suggesting a role for calcification in the pathogenesis AVF failure.

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