Amdahl, Matthew B.

Abstract Aims Chronic kidney disease (CKD) is common in patients with heart failure (HF) with preserved ejection fraction (HFpEF), and its presence is associated with more severe echocardiographic abnormalities and poorer outcomes through unclear mechanisms. CKD-associated endothelial dysfunction, inflammation, and activation of profibrotic pathways could worsen pulmonary vascular disease (PVD) in HFpEF, but such relationships have not been explored. Methods Consecutively evaluated patients with HFpEF undergoing invasive haemodynamic cardiopulmonary exercise testing were stratified by baseline kidney function to characterize potential differences in pulmonary vascular loading, haemodynamics, cardiopulmonary reserve, and outcomes based upon the presence and severity of kidney dysfunction. Results Of 925 patients with HFpEF, 319 (34.5%) had estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2. Patients with more severe kidney dysfunction were older and more likely to have diabetes, atrial fibrillation, and hypertension. At rest, reduced kidney function was associated with lower haemoglobin, higher biventricular filling pressures, and lower cardiac output, but the severity of kidney dysfunction was most conspicuously associated with worsening PVD, evidenced by increasing pulmonary arterial (PA) pressures due to marked increases in pulmonary vascular resistance (PVR) as kidney dysfunction progressed (median [IQR] 1.3 [0.86, 1.88] to 2.8 [2.0, 3.8] WU from eGFR ≥ 90 to eGFR < 30, P < .001), along with progressively lower PA compliance (PAC, 4.7 [3.6, 5.8] to 2.2 [1.8, 3.4] ml/mmHg from eGFR ≥ 90 to eGFR < 30, P < .001). With exercise, differences in the severity of PVD became even more striking, with more severe elevation in PA pressures and PVR, and lower PA compliance, leading to lower transmural left-sided distending pressures, with no difference in exertional PA wedge pressure. Patients with worse kidney dysfunction displayed the most dramatic cardiac output limitations with exercise, which along with more severe anaemia and markedly reduced O2 delivery, caused marked impairment in aerobic capacity. Worsening kidney function was associated with a striking gradient of increased risk of a composite of all-cause death and HF hospitalization [ranging from HR 2.38 (95% CI 1.01–5.59) for eGFR 60–90 to HR 16.77 (95% CI 6.65–42.28) for eGFR < 30 (vs. reference eGFR ≥ 90)]. Conclusions Kidney dysfunction in patients with HFpEF is characterized by more severe PVD at rest and with exercise, leading to reduced cardiac output reserve, impaired exercise capacity, and increased risk for adverse events. Further study is warranted to better understand causal relationships between CKD and PVD, and determine whether novel therapies to improve kidney function might target these impairments to improve clinical status.

The clinical benefit of blood transfusion is undeniable, and yet reliance on donated blood products has several shortcomings. These include risks of supply shortages due to reliance on volunteer donors, short storage life, and potential infectious disease transmission. Immune response complications to donated blood cannot be completely avoided, despite significant advances in testing. Many of these limitations are exacerbated in low-income countries. For decades, cell-free hemoglobin-based blood substitutes have been developed and tested as potential substitutes for red blood cell transfusions. Early studies found that purified, native hemoglobin exhibited significant safety risks, such as hypertension from excessive vasoconstriction and evidence of multiple organ toxicities. These effects are likely in part due to the reactive heme center, which will scavenge nitric oxide, generate reactive oxygen species, and may drive sterile inflammation. Numerous strategies have been explored to further modify hemoglobin in the hope of creating a safe and well-tolerated blood substitute. Despite some promising results in preliminary studies, large-scale clinical trials have continued to show elevated rates of adverse events and/or a failure to meet specified clinical endpoints. As a result, no hemoglobin-based oxygen carrier (HBOC) has obtained US Food and Drug Administration approval for clinical use. This review focuses on the history of HBOC development, the lessons that have been learned from prior failures of HBOC programs, and the status of ongoing artificial oxygen carrier development efforts.