Low Flow-Mediated Constriction: Prevalence, Impact, and Physiological Determinant

Flow-mediated dilation (FMD) is a surrogate marker for endothelial function. In the FMD procedure, arterial response during cuff inflation is not taken into consideration yet studies have demonstrated vasoconstriction, vasodilation, and no change in the brachial artery during cuff inflation. The term low flow-mediated constriction (L-FMC) has been introduced to describe the vasoconstriction that occurs in some individuals during inflation of the cuff. PURPOSE: To determine 1) if brachial artery response during cuff inflation differed in a population with varied coronary artery disease (CAD) risk factor profiles, 2) the impact of this response on the subsequent calculation of FMD, and 3) the role of arterial stiffness in this variable response. METHODS: Low flow-mediated constriction (L-FMC), “traditional” FMD, and “modified” FMD that accounts for L-FMC by using inflation diameter in place of baseline diameter in calculating FMD, were studied in a total of 46 subjects. Subjects varied in age (38-62 years) and risk factor profiles for coronary artery disease. RESULTS: During cuff inflation, brachial artery responses varied widely from -5.6% (vasoconstriction) to 5.0% (vasodilation). When subjects were divided into healthy versus multiple risk factors (n=34), L-FMC and FMD were not different between the groups but modified FMD was significantly different (p=0.02). L-FMC was modestly but significantly associated with FMD (r=0.41) and positively correlated with brachial artery pulse wave velocity (r=0.30). CONCLUSION: Our results indicate that brachial artery responses to inflation of the cuff are very variable and are associated with arterial stiffness and that accounting for so-called L-FMC may provide a more comprehensive assessment of endothelial vasodilatory function

Targeting hypoxia-inducible factor-1α (HIF-1α) in combination with antiangiogenic therapy: a phase I trial of bortezomib plus bevacizumab.

PurposeWe hypothesized that bortezomib, an agent that suppresses HIF-1α transcriptional activity, when combined with bevacizumab, would obviate the HIF-1α resistance pathway. The objectives of this phase I trial were to assess safety and biological activity of this combination.Experimental designPatients with advanced, refractory malignancies were eligible. Patients received bevacizumab and bortezomib (3-week cycle) with dose expansions permitted if responses were seen and for assessing correlates. Pharmacodynamic assessment included plasma VEGF, VEGFR2, 20S proteasome inhibition, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and HIF-1α tumor expression.ResultsNinety-one patients were treated (median=6 prior treatments). The FDA-approved doses of both drugs were safely reached, and the recommended phase 2 dose (RP2D) is bevacizumab 15 mg/kg with bortezomib 1.3 mg/m(2). Four patients attained partial response (PR) and seven patients achieved stable disease (SD) ≥ 6 months (Total SD ≥ 6 months/PR=11 (12%)). The most common drug-related toxicities included thrombocytopenia (23%) and fatigue (19%). DCE-MRI analysis demonstrated no dose-dependent decreases in K(trans) although analysis was limited by small sample size (N=12).ConclusionCombination bevacizumab and bortezomib is well-tolerated and has demonstrated clinical activity in patients with previously treated advanced malignancy. Pharmacodynamic assessment suggests that inhibition of angiogenic activity was achieved

Associations of resting heart rate with endothelium-dependent vasodilation and shear rate

Heart rate is an independent risk factor for cardiovascular disease and a hemodynamic factor that can modulate blood flow as it affects the frequency of shear stimuli acting on the arterial wall. However, the association between heart rate and endothelium-dependent vasodilation remains highly controversial. We determined the association between heart rate at rest and endothelium-dependent vasodilation in 98 apparently healthy adults (18–63 years). The mild and positive association between heart rate and flow-mediated dilation (FMD) was no longer significant when age and sex or baseline diameter were controlled for. The path analyses revealed that heart rate was not directly related to FMD but the association was indirectly mediated by shear rate, which was confirmed by a bias-corrected bootstrap 95% CIs (0.0157–0.1056). We concluded that even though heart rate and endothelium-dependent vasodilation were associated with shear rate, there was no independent relation between heart rate and FMD