Combined therapy with direct and indirect angiogenesis inhibition results in enhanced antiangiogenic and antitumor effects.

The multifaceted nature of the angiogenic process in malignant neoplasms suggests that protocols that combine antiangiogenic agents may be more effective than single-agent therapies. However it is unclear which combination of agents would be most efficacious and will have the highest degree of synergistic activity while maintaining low overall toxicity. Here we investigate the concept of combining a "direct" angiogenesis inhibitor (endostatin) with an "indirect" antiangiogenic compound [SU5416, a vascular endothelial growth factor receptor 2 (VEGFR2) receptor tyrosine kinase (RTK) inhibitor]. These angiogenic agents were more effective in combination than when used alone in vitro (endothelial cell proliferation, survival, migration/invasion, and tube formation tests) and in vivo. The combination of SU5416 and low-dose endostatin further reduced tumor growth versus monotherapy in human prostate (PC3), lung (A459), and glioma (U87) xenograft models, and reduced functional microvessel density, tumor microcirculation, and blood perfusion as detected by intravital microscopy and contrast-enhanced Doppler ultrasound. One plausible explanation for the efficacious combination could be that, whereas SU5416 specifically inhibits vascular endothelial growth factor signaling, low-dose endostatin is able to inhibit a broader spectrum of diverse angiogenic pathways directly in the endothelium. The direct antiangiogenic agent might be able to suppress alternative angiogenic pathways up-regulated by the tumor in response to the indirect, specific pathway inhibition. For future clinical evaluation of the concept, a variety of agents with similar mechanistic properties could be tested.

Acute effects of Finnish sauna and cold-water immersion on haemodynamic variables and autonomic nervous system activity in patients with heart failure.

BACKGROUND: The haemodynamic response to Finnish sauna and subsequent cold-water immersion in heart failure patients is unknown. METHODS: Haemodynamic response to two consecutive Finnish sauna (80℃) exposures, followed by a final head-out cold-water immersion (12℃) was measured in 37 male participants: chronic heart failure (n = 12, 61.8 ± 9.2 years), coronary artery disease (n = 13, 61.2 ± 10.6 years) and control subjects (n = 12, 60.9 ± 8.9 years). Cardiac output was measured non-invasively with an inert gas rebreathing method prior to and immediately after the first sauna exposure and after cold-water immersion, respectively. Blood pressure was measured before, twice during and after sauna. The autonomic nervous system was assessed by power spectral analysis of heart rate variability. Total power, low-frequency and high-frequency components were evaluated. The low frequency/high frequency ratio was used as a marker of sympathovagal balance. Sauna and cold-water immersion were well tolerated by all subjects. RESULTS: Cardiac output and heart rate significantly increased in all groups after sauna and cold-water immersion (p < 0.05), except for coronary artery disease patients after sauna exposure. Systolic blood pressure during sauna decreased significantly in all groups with a nadir after 6 min (all p < 0.05). Cold-water immersion significantly increased systolic blood pressure in all groups (p < 0.05). No change in the low/high frequency ratio was found in chronic heart failure patients. In coronary artery disease patients and controls a prolonged increase in low frequency/high frequency ratio was observed after the first sauna exposure. CONCLUSIONS: Acute exposure to Finnish sauna and cold-water immersion causes haemodynamic alterations in chronic heart failure patients similarly to control subjects and in particular did not provoke an excessive increase in adrenergic activity or complex arrhythmias.

Combined aerobic/inspiratory muscle training vs. aerobic training in patients with chronic heart failure: The Vent-HeFT trial: a European prospective multicentre randomized trial.

AIMS: Vent-HeFT is a multicentre randomized trial designed to investigate the potential additive benefits of inspiratory muscle training (IMT) on aerobic training (AT) in patients with chronic heart failure (CHF). METHODS AND RESULTS: Forty-three CHF patients with a mean age of 58 ± 12 years, peak oxygen consumption (peak VO2 ) 17.9 ± 5 mL/kg/min, and LVEF 29.5 ± 5% were randomized to an AT/IMT group (n = 21) or to an AT/SHAM group (n = 22) in a 12-week exercise programme. AT involved 45 min of ergometer training at 70-80% of maximum heart rate, three times a week for both groups. In the AT/IMT group, IMT was performed at 60% of sustained maximal inspiratory pressure (SPImax ) while in the AT/SHAM group it was performed at 10% of SPImax , using a computer biofeedback trainer for 30 min, three times a week. At baseline and at 3 months, patients were evaluated for exercise capacity, lung function, inspiratory muscle strength (PImax ) and work capacity (SPImax ), quality of life (QoL), LVEF and LV diameter, dyspnoea, C-reactive protein (CRP), and NT-proBNP. IMT resulted in a significantly higher benefit in SPImax (P = 0.02), QoL (P = 0.002), dyspnoea (P = 0.004), CRP (P = 0.03), and NT-proBNP (P = 0.004). In both AT/IMT and AT/SHAM groups PImax (P < 0.001, P = 0.02), peak VO2 (P = 0.008, P = 0.04), and LVEF (P = 0.005, P = 0.002) improved significantly; however, without an additional benefit for either of the groups. CONCLUSION: This randomized multicentre study demonstrates that IMT combined with aerobic training provides additional benefits in functional and serum biomarkers in patients with moderate CHF. These findings advocate for application of IMT in cardiac rehabilitation programmes.