Background: Proteomics have already provided novel insights into the pathophysiology of heart failure (HF) with reduced ejection fraction. Previous studies have evaluated cross-sectional protein signatures of HF, but few have characterized proteomic changes following HF with reduced ejection fraction treatment with ARNI (angiotensin receptor/neprilysin inhibitor) therapy or left ventricular assist devices. Methods: In this retrospective omics study, we performed targeted proteomics (N=625) of whole blood sera from patients with American College of Cardiology/American Heart Association stage D (N=29) and stage C (N=12) HF using proximity extension assays. Samples were obtained before and after (median=82 days) left ventricular assist device implantation (stage D; primary analysis) and ARNI therapy initiation (stage C; matched reference). Oblique principal component analysis and point biserial correlations were used for feature extraction and selection; standardized mean differences were used to assess within and between-group differences; and enrichment analysis was used to generate and cluster Gene Ontology terms. Results: Core sets of proteins were identified for stage C (N=9 proteins) and stage D (N=18) HF; additionally, a core set of 5 shared HF proteins (NT-proBNP [N-terminal pro-B type natriuretic peptide], ESM [endothelial cell-specific molecule]-1, cathepsin L1, osteopontin, and MCSF-1) was also identified. For patients with stage D HF, moderate (δ, 0.40–0.60) and moderate-to-large (δ, 0.60–0.80) sized differences were observed in 8 of their 18 core proteins after left ventricular assist devices implantation. Additionally, specific protein groups reached concentration levels equivalent ( g <0.10) to stage C HF after initiation on ARNI therapy. Conclusions: HF with reduced ejection fraction severity associates with distinct proteomic signatures that reflect underlying disease attributes; these core signatures may be useful for monitoring changes in cardiac function following initiation on ARNI or left ventricular assist device implantation.
Glucocorticoids increase osteoclast-mediated bone resorption while inhibiting osteoblast proliferation and differentiation. Bisphosphonates are indicated for glucocorticoid-induced osteoporosis (GIOP) prophylaxis but are not recommended with severe renal impairment. Safety of alternatives is unclear in immunosuppressed dialysis patients and may not be economical. No prior publication has described the use of bisphosphonates for GIOP in transplant patients on dialysis. Case Report: We report five cases of cardiac transplant patients on hemodialysis (HD) and long-term prednisone who received up to four doses of pamidronate 30 mg intravenously (IV) in the first year post-transplant. Two of the five patients went on to have renal recovery. There were no episodes of hypocalcemia after adjusting for albumin. Three patients did not demonstrate decreased BMD at one year or more post-transplant. One patient progressed from osteopenia to osteoporosis, and another had osteopenia post-transplant but with unknown baseline. Summary: Bisphosphonates are first line for preventing osteoporosis from long-term glucocorticoids; however, their role in patients with renal impairment is unclear. Reduced elimination increases risk of hypocalcemia though HD may remove some bisphosphonates. Though timing of dialysis after administration was not evaluated here, there were no episodes of hypocalcemia following thirteen total pamidronate doses. Additionally, rapid IV administration can cause acute renal failure due to accumulation in the renal tubules. Doses were given over four hours to mitigate risk, and two patients had renal recovery despite this possibility. In conclusion, low-dose pamidronate may be well tolerated by dialysis dependent SOT patients and provide a cost effective GIOP option. Additional studies are needed to determine the most effective and safe dose in this population.
Introduction: The COVID-19 Pandemic has mandated limiting routine visit frequency for patients with chronic cardiovascular (CV) diseases. In patients with heart failure (HF) followed longitudinally, the period of clinical trial participation provides an opportunity to evaluate the influence of high-frequency per-protocol in-person visits compared to less frequent routine visits during longitudinal clinical care. Hypothesis: Patients enrolled in clinical trials will have a lower CV and HF event rates during periods of trial enrollment than during non-trial periods. Methods: We examined clinical characteristics, CV and HF hospitalization rates, and outcomes in patients with HF receiving longitudinal HF care at a single center. We evaluated hospitalization rates during the 1-year preceding trial enrollment and hospitalization and death rates during enrollment in clinical trials and for up to 1 year following trial completion. Results: Among the 121 patients enrolled in HF clinical trials, 72% were HFrEF (age 62±11, 19% females, BMI 30.4±6.0, LVEF 25±7, NYHA 2.7±0.6, NT-proBNP 2336±2671) and 28% were HFpEF (age 69±9, BMI 32.1±5.5, 29% females, LVEF 60±10, NYHA 2.4±0.5, NT-proBNP 957±997). Average clinical trial exposure was 8±6.6 months. Per-protocol visit frequency was 16±7 per year during clinical trial enrollment. In the one-year pre-trial period, compared to the within-trial period, CV hospitalizations were 0.88/patient-year vs. 0.32/patient-year (p<0.001) and HF hospitalizations were 0.63/patient-year and 0.24/patient-year (p<0.001), with a mortality rate of 0.04/patient-year during trial participation. In the period of up-to 1 year following the end of trial enrollment CV and HF hospitalizations were intermediate at 0.51/patient-year and 0.27/patient-year with an annualized incremental mortality rate of 0.03/patient-year. Conclusion: In HF patients followed longitudinally at a single center, periods of clinical trial enrollment were associated with high visit frequency and lower CV and HF hospitalization rates. These findings highlight the potential benefits of trial enrollment and high-frequency visits for HF patients at a time when routine visit frequency is being carefully considered during the COVID-19 Pandemic.
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