The relative sensitivity and unexplained detection rate of changes in intrathoracic impedance has not been compared with standard heart failure (HF) monitoring using daily weight changes. The Fluid Accumulation Status Trial (FAST) prospectively followed 156 HF patients with implanted cardioverter-defibrillator or cardiac resynchronization therapy defibrillator devices modified to record daily changes in intrathoracic impedance in a blinded fashion for 537±312 days. Daily impedance changes were used to calculate a fluid index that could be compared with a prespecified threshold. True positives were defined as adjudicated episodes of worsening HF occurring within 30 days of a fluid index above threshold or an acute weight gain. Unexplained detections were defined as threshold crossings or acute weight gains not associated with worsening HF. Impedance measurements were performed on >99% of follow-up days, compared with only 76% of days for weight measurements. Sixty-five HF events occurred during follow-up (0.32/patient-year). Forty HF events were detected by impedance but not weight, whereas 5 were detected by weight but not impedance. Sensitivity was greater (76% vs 23%; P<.0001) and unexplained detection rate was lower (1.9 vs 4.3/patient-year; P<.0001) for intrathoracic impedance monitoring at the threshold of 60Ω days compared with acute weight increases of 3 lbs in 1 day or 5 lbs in 3 days and also over a wide range of fluid index and weight thresholds. The sensitivity and unexplained detection rate of intrathoracic impedance monitoring was superior to that seen for acute weight changes. Intrathoracic impedance monitoring represents a useful adjunctive clinical tool for managing HF in patients with implanted devices.

Fluid flow and the associated shear stress play a critical role in vascular growth and remodeling. Recent data suggest that increased endothelial cell expression of platelet-derived growth factor (PDGF) A- and B-chain by flow may participate in these events. In the present study, we examined the mechanism for flow-induced PDGF expression, focusing on protein kinase C (PKC). Bovine aortic endothelial cells were exposed to flow (shear stress = 30 dyn/cm2) in a parallel-plate flow chamber. Increases in PDGF B-chain, but not PDGF A-chain, were observed within 3 h, maximal within 6 h (13-fold increase), and sustained for 24 h. PKC appeared to be involved because phorbol 12-myristate 13-acetate induced PDGF B-chain mRNA. Activation of PKC alone, however, was insufficient to induce PDGF mRNA because the selective PKC activator, 1-oleoyl-2-acetyl-sn-glycerol, did not induce PDGF expression. A PKC-independent pathway was suggested by the fact that inhibition of PKC (downregulation with phorbol 12,13-dibutyrate or exposure to staurosporine) failed to block PMA or flow-induced PDGF B-chain expression. These results demonstrate flow-induced PDGF B-chain expression in endothelial cells that appears to be mediated, in part, by a PKC-independent pathway.

Angiotensin-converting enzyme (ACE) activity plays a central role in vessel growth and remodeling as shown by the fact that ACE inhibitors reduce neointimal proliferation after rat carotid injury. To investigate the mechanisms that regulate smooth muscle cell ACE expression, we studied the effects of steroids on ACE activity and mRNA in cultured rat aortic smooth muscle cells. ACE activity was present at low levels independent of growth state. In response to the glucocorticoid dexamethasone (100 nmol/L for 72 hours), ACE activity (hydrolysis of [3H]benzoyl-Phe-Ala-Pro) increased 10.1 +/- 3.1-fold. The increase in activity occurred within 12 hours and peaked after 72 hours of treatment. The increase in ACE activity was specific for glucocorticoids and paralleled their potency (dexamethasone > hydrocortisone = prednisolone). Dexamethasone increased the steady-state level of ACE mRNA in a concentration-dependent manner (21.4 +/- 0.4-fold at 100 nmol/L for 72 hours). Dexamethasone stimulation of ACE expression appeared to be due to both increased transcription and stabilization of ACE enzyme mRNA. This was suggested by the finding that dexamethasone stimulated nuclear run-on expression of ACE mRNA by only threefold, in contrast to the 21-fold increase in steady-state mRNA. These findings establish that ACE is a dynamically regulated enzyme in rat aortic smooth muscle cells. In addition, the present findings suggest an important role for stress steroids in the vascular response to injury in vivo.

In the SMART-SF trial, the predetermined safety performance goal was met, demonstrating the safety and acute effectiveness of the THERMOCOOL SMARTTOUCH® SF Catheter for PAF ablation.

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