Background-A respiratory cycle for nitric oxide (NO) would involve the formation of vasoactive metabolites between NO and hemoglobin during pulmonary oxygenation. We investigated the role of these metabolites in hypoxic tissue in vitro and in vivo in healthy subjects and patients with congestive heart failure (CHF compared with relaxations induced at 95% (PϽ0.05), consistent with an allosteric mechanism of hypoxic vasodilation. We also measured transpulmonary gradients of NO metabolites in healthy control subjects and in patients with CHF. In CHF patients but not control subjects, levels of SNO-Hb increase from 0.00293Ϯ0.00089 to 0.00585Ϯ0.00137 mol NO/mol hemoglobin tetramer (Pϭ0.005), whereas HbFeNO decreases from 0.00361Ϯ0.00109 to 0.00081Ϯ0.00040 mol NO/mol hemoglobin tetramer (Pϭ0.03) as hemoglobin is oxygenated in the pulmonary circulation. These metabolite gradients correlated with the hemoglobin O 2 saturation gradient (PϽ0.05) and inversely with cardiac index (PϽ0.05) for both CHF patients and control subjects. Conclusions-We confirm that RBC-bound NO mediates hypoxic vasodilation in vitro. Transpulmonary gradients of hemoglobin-bound NO are evident in CHF patients and are inversely dependent on cardiac index. Hemoglobin may transport and release NO bioactivity to areas of tissue hypoxia or during increased peripheral oxygen extraction via an allosteric mechanism.

Undiagnosed familial hypercholesterolaemia carries a high risk of cardiovascular disease, which is easily preventable with pharmacotherapy, if individuals are appropriately diagnosed, and affected family members identified. The use of DNA testing is cost-effective and allows for efficient cascade testing. This has implications for local services and highlights unmet educational and clinical requirements in clinical lipidology.

Familial hypercholesterolemia (FH) is an autosomal co-dominant disorder characterized by a marked elevation of serum low-density lipoprotein (LDL) cholesterol (LDL-C) concentration, which in turn is associated with a greatly increased risk of premature cardiovascular disease. International consensus recommends the use of statins as the first line of treatment for patients with this condition. However, homozygote FH patients with persistently elevated LDL-C levels are usually resistant to multiple-drug therapy. Fortunately, LDL apheresis (or simply 'lipoprotein apheresis') provides a treatment option for patients who are refractory or intolerant to lipid-lowering medications, or if there is progressive cardiovascular disease despite maximal drug therapy. Lipoprotein apheresis is an extracorporeal LDL-C-lowering treatment similar in concept to renal dialysis. There are now five main methods for extracorporeal lipoprotein apheresis in use, namely dextran sulfate adsorption (DSA), heparin extracorporeal LDL precipitation (HELP), polyacrylate full blood adsorption (PFBA or DALI® system) using hemoperfusion, immunoadsorption, and filtration plasmapheresis. Lipoprotein apheresis has been shown to be successful in reducing LDL-C levels, as well as levels of lipoprotein(a) [Lp(a)], a prothrombotic proatherogenic lipoprotein. In contrast, however, lipoprotein apheresis seems to have a smaller effect in preventing atherosclerosis progression, thus suggesting that a major component of the reduction in cardiovascular events may be mediated by mitigating Lp(a) levels. Side effects are infrequent and mild, and have mainly consisted of lightheadedness, nausea, vomiting, and hypotension. As these are often bradykinin-mediated and associated with concomitant ACE inhibitor use, angiotensin type 2 receptor antagonists should be used instead of ACE inhibitors with DALI and PFBA. Nevertheless, there is scope for wider application of lipoprotein apheresis. The high cost and invasive nature of lipoprotein apheresis limits uptake; however, it is an important treatment modality that should be considered in carefully selected patients. National and international registries compiling outcome data for lipoprotein apheresis need to be established to help expand the evidence base regarding its effectiveness.

For the first time in human subjects across the resting coronary circulation we reveal significant re-apportionment of NO between metabolite species which correlate with haemoglobin oxygen saturation. These changes occur even within the transit time of blood across this single vascular bed. We demonstrate no net loss/gain of NO from the total metabolite pool across the coronary circulation even where NO biosynthesis is inhibited.