Anaemia Associated with Heart Failure
Iron deficiency (serum ferritin < 100ug/l or 100-300 ug/l+ transferrin sat <20%) frequently co-exists with chronic heart failure (CHF), irrespective of anaemia, and is related to disease severity and low grade inflammation. Anaemia (hb < or = 12g/dl) is present in approximately 10-12 % of CHF patients. The renaissance trial showed that better survival and less hospitalisation was linked to higher baseline HB in CHF patients.
Elevated cytokines, ace-inhibitors, and beta-blockers have all been associated with reductions in HB. Anaemia reduces the oxygen-carrying capacity of blood and trials are now investigating correcting anaemia in CHF.
A trial with darbepoetin –alpha and 200mg daily iron replacement in 319 heart failure patients with entry HB <12>9 failed to show clinical benefit despite an increase in HB over 9 weeks. The target of 14g/dl as a target HB in the trial may have been too low. A larger trial is needed.
A trial performed in the UK and Poland with weekly 200mg IVI iron infused over 30 minutes in 35 patients caused a significant increase in Ferritin but little change in HB. In the group that were anaemic on entry, the therapy appeared to increase VO2MAX and patients' sense of well being
Anaemia (HB<12g/dl) is associated with a worse prognosis in patients with acute heart failure.
Further studies are required for optimal anaemia diagnostic criteria in CHF, and whether iron repletion can be a therapeutic option. A large randomised trial is currently being performed.
Watch this space!
Aspects of interest from ESC Heart Failure Meeting, Helsinki (17-20 June 2006)
The myopathy of heart failure is generalised, involving skeletal muscle too. The PCr (Phosphocreatine)/ATP ratio is predictive of mortality in heart failure. The mitochondria are a source of PCr. On arrival at the myofilament, ADP is converted into ATP releasing Cr to return back to the mitochondria and thus completing the cycle. As ejection fraction worsens, so does the PCr/ATP ratio. It is thought that the increased free fatty acid metabolism in the failing heart acts on the DNA to produce more uncoupling proteins in the mitochondria, and thus decreased PCr production. Cardiac MRI can measure PCr levels.
The above raises the possibility that inhibiting fatty acid oxidation, would improve prognosis in heart failure. This is not clear at present, however. One study showed feeding rats a high fat diet caused improved survival in heart failure.
The assessment of the severity of mitral regurgitation (MR) by echo remains difficult. The degree of MR is underestimated by echo when systemic blood pressure is low, in the presence of a small left atrium and with a tachycardia. A vena contracta measuring > 7 mm, a reversal of the S wave on pulmonary venous flows and density of the MR jet, all point towards severity. A centrally directed jet, however, may give the wrong impression of severe MR.
An important therapeutic point is to AVOID POSITIVE INOTROPES in acute mitral regurgitation. This increases contractility and regurgitant volume.
Adenosine increases proximal renal tubular sodium reabsorption. Two randomised trials in heart failure have been performed using A1 receptor antagonists. CKI-201 gave a daily two-hour infusion for up to three days and measured six-hour urine volume as a primary end point. They found a trend to decreased diuretic dose, and fewer days on infusion in the active group. There was no better renal function in the two groups. CKI-202 used a higher dose and looked at urine volume in the first 12 hours and Creatinine Clearance (Cr Cl) in 36 patients with refractory heart failure. Urine output was increased in the first six hours with no change in Cr Cl in the two groups, and no more side effects. These drugs can precipitate seizures by lowering the seizure threshold. 30 mg appears to be optimal dose. The PROTECT trial is due to start end of 2006.
The extra-cellular matrix in the heart is very important for the survival of the myocyte. We forget that 70-75% of heart cells are NON-myocytes, including endothelial cells, smooth muscle cells, fibroblasts, collagen, etc. In heart failure there is a change in collagen structure and turnover stimulated by endothelin, angiotensin, aldosterone etc. Both beta-blockers and ACEI reduce collagen content in the heart. Preventing collagen breakdown may be beneficial, however. Collagen is degraded by a family of more than 20 zinc-related enzymes called metallo-proteinases (MMPs). A trial of a MMP inhibitor is currently being performed (PREMIER study) involving 250 STEMI patients in the USA, Canada and Poland.
Fabry’s disease involves increased glycolipid accumulation in various organs of the body and there is a cardiac variant. All heart cells are involved including endocardium, myocardium and the interstitium. The disease presents with diastolic and systolic dysfunction, as well as conduction disease. This may be the diagnosis in up to 12% of females with late onset HCM; non-obstructive, obstructive or apical. A good echo sign is the binary appearance of the LV endocardial border - a hyperechogenic line between endo and myocardium. Enzyme replacement therapy with agalsidase alpha may help.
Atrial fibrillation remains an increasing problem in the management of heart failure patients. A resting heart rate of 60-80 beats/min and 90-115 with exercise is deemed good rate conrol. The AF-CHF study due out in 2007/2008 will help resolve some of the issues of rate control vs. rhythm control in heart failure specifically.
Hyperuricemia seen in heart failure may not be a benign phenomenon. Prognosis appears to be related to urate levels in heart failure and it remains one of the cheaper and strongest predictors of mortality in heart failure. Levels greater than 0.8 predict death in three years. The increased levels seen may relate to increased production by increased cell death and insulin resistance and increased XO activity related to tissue hypoxia and immune activation, Imapired renal function and diuretic therapy also raise urate levels. It is important to remember that the development of allopurinol (a competitive inhibitor of XO) got the Nobel Prize in 1963. An active metabolite is oxypurinol. The OPT-CHF study using oxypurinol for 24 weeks in Class III-IV patients was ended prematurely because of non-beneficial effects. A direct XO inhibitor may be used in future trials.