Cardiac resynchronization therapy improves minute ventilation/carbon dioxide production slope and skeletal muscle capillary density without reversal of skeletal muscle pathology or inflammation.

AIMS: We evaluated the effects of cardiac resynchronization therapy (CRT) on skeletal muscle pathology and inflammation in patients with heart failure. METHODS AND RESULTS: Stable patients (n = 21, 14 males, mean age 70 ± 7 years) with symptomatic heart failure (mean left ventricular ejection fraction 24 ± 6%) and an indication for CRT were included. Ergospirometry, skeletal muscle open biopsy, and blood sampling were performed prior to implantation and after 6 months of CRT. After CRT there was a reduction in both left ventricular end-diastolic diameter (LVEDD; 6.8 ± 0.8 vs. 6.3 ± 0.7 cm, P < 0.001) and native QRS duration (D) minus biventricular paced QRSD (172.9 ± 23 vs. 136.3 ± 23 ms, P ≤ 0.001). These changes were associated with an increase in peak slope oxygen uptake (consumption) (VO2) (13.3 ± 2.2 vs. 14.5 ± 2.6 mL/kg/min, P = 0.07) and an improvement in the minute ventilation/carbon dioxide production slope (VE/VCO2) slope (41.6 ± 7.4 vs. 39.1 ± 5.6, P = 0.012). There were no statistically significant changes in levels of pro-inflammatory cytokines, in mediators of mitochondrial biosynthesis or skeletal muscle pathology, except for an increase in skeletal muscle capillary density (4.5 ± 2.4 vs. 7.7 ± 3.3%, P = 0.002). Both the reduction of QRS duration and the increase in peak VO2 correlated significantly with the change in mitochondrial density (r = 0.57, P = 0.008 and r = 0.54, P = 0.027, respectively). CONCLUSION: Cardiac resynchronization therapy, with improved functional status and reduced LVEDD resulted in increased peak VO2, improvement in VE/VCO2 slope and capillary density in skeletal muscle, with no reduction in systemic pro-inflammatory cytokines, increase in intramuscular levels of mediators of mitochondrial biosynthesis or improvement in skeletal muscle ultrastructure per se. ClinicalTrials.gov Identifier: NCT01019915.

Neuropathological changes in the brain of pigs with acute liver failure.

OBJECTIVE: Cerebral edema is a serious complication of acute liver failure (ALF), which may lead to intracranial hypertension and death. An accepted tenet has been that the blood-brain barrier is intact and that brain edema is primarily caused by a cytotoxic etiology due to hyperammonemia. However, the neuropathological changes in ALF have been poorly studied. Using a well characterized porcine model we aimed to investigate ultrastructural changes in the brain from pigs suffering from ALF. MATERIALS AND METHODS: Sixteen female Norwegian Landrace pigs weighing 27-35 kg were randomised into two groups: ALF (n = 8) and sham operated controls (n = 8). ALF was induced with an end-to-side portacaval shunt followed by ligation of the hepatic arteries. Biopsies were harvested from three different areas of the brain (frontal lobe, cerebellum, and brain stem) following eight hours of ALF and analyzed using electron microscopy. RESULTS: Profound perivascular and interstitial edema were found in all three areas. Disruption of pericytic and astrocytic processes were seen, reflecting breakdown/lesion of the blood-brain barrier in animals suffering from ALF. Furthermore, neurons and axons were edematous and surrounded by vesicles. Severe damage to Purkinje neuron (necrosis) and damaged myelin were seen in the cerebellum and brain stem, respectively. Biopsies from sham operated animals were normal. CONCLUSIONS: Our data support the concept that vasogenic brain edema plays an important role in the development of intracranial hypertension in pigs with ALF.