spring cleaning

I know, I said a big post on lupus was coming, imaginary blog readers. But I haven't been able to read the reviews yet. So let me leave you with the few other interesting pieces I've read in the past few weeks before I vanish until December.

Eplerenone in CHF (the EMPHASIS-HF study)

Yeah, there's nothing that's going to rock your world in this recent NEJM study; following the RALES study which showed an indication for spironolactone treatment in patients with class III/IV CHF, this study looked at almost 3,000 patients with class II CHF (mild symptoms only) and an EF of no greater than 35% and found a significant morbidity and mortality benefit. Yeah. If you really want to see if mineralocorticoid antagonism works as preventive therapy, look in patients who already don't have frank evidence of pathological remodeling. Aren't these patients on the doorstep of class III heart failure already? Boo.

Tonic inhibition and recovery after stroke

Ischemic strokes are a leading cause of morbidity and mortality, especially in the elderly, whose risk factors for stroke (hypertension, diabetes, hyperlipidemia) tend to be more prevalent. Aggressive risk factor control clearly reduces the risk of developing a stroke, or a future stroke after one happens. But almost nothing has been shown to reduce functional impairment caused by a stroke after it happens. Really, the only effective intervention is early rehabilitation, which has been shown in multiple randomized control studies to improve functionality by inducing cortical remodeling following a stroke. Subsequent studies have shown that the cortical remodeling that drives partial recovery of function following a stroke is not the infarcted tissue but rather the peri-infarct tissue. Excitation of peri-infarct tissue following stroke drives long-term potentiation, resulting in effective remodeling. However, long-term potentiation requires sustained synaptic neurotransmission, which is limited in peri-infarct cortex. Why exactly is this?

Count on Nature to give us the answers. A letter published a few weeks ago describes a breakthrough in understanding the physiologic brakes on peri-infarct cortical remodeling. The study focuses on GABA, an inhibitor neurotransmitter with both activity that is both synaptic (released in response to stimulus) and tonic (released at a constant rate to set a post-synaptic excitability threshold). Tonic GABA release has been shown to oppose long term potentiation and memory. The authors of the above study wondered if similar GABA-mediated tonic inhibition repressed cortical remodeling following a stroke.

Indeed, tonic GABA-mediated inhibition was found to be markedly increased in peri-infarct cortex following photothrombotic stroke in mice. This increased GABA tone increased the excitability threshold and was completely reversed by the GABA inhibitor gabazine.

Having established the role for GABA in post-infarct tonic inhibition, the authors then addressed whether GABA inhibition following stroke could restore functional capacity. Indeed, GABA blockade improved foot paw symmetry during locomotion and decreased foot faults during measured tasks.

But is there actual utility to GABA blockade in pts who undergo a stroke? Well, its complicated. The main problem is that GABA mediated inhibition immediately following a stroke limits infarct size; accordingly, GABA blockade improved murine mortality when given 3 days after a stroke but not when given immediately afterwards. Furthermore, prolonged GABA inhibition eventually led to worsening of functional performance. While this calls for careful modulation of GABA inhibition, it actually provides a potentially clincially applicable regimen: initiation of therapy a few days after a stroke, when symptoms are sure to be present, and stopping therapy after a limited amount of time (although improvements in functional status are not completely sustained after treatment is withdrawn.

Uh, CX3CR1 will have to wait for a time when I'm not actively going into a coma.