Continuous aortic flow augmentation - A pilot study of hemodynamic and renal responses to a novel percutaneous intervention in decompensated heart failure

Background - Diminished aortic flow may induce adverse downstream vascular and renal signals. Investigations in a heart failure animal model have shown that continuous aortic flow augmentation ( CAFA) achieves hemodynamic improvement and ventricular unloading, which suggests a novel therapeutic approach to patients with heart failure exacerbation that is inadequately responsive to medical therapy. Methods and Results - We studied 24 patients ( 12 in Europe and 12 in the United States) with heart failure exacerbation and persistent hemodynamic derangement despite intravenous diuretic and inotropic and/or vasodilator treatment. CAFA ( mean +/- SD 1.34 +/- 0.12 L/min) was achieved through percutaneous ( n = 19) or surgical ( n = 5) insertion of the Cancion system, which consists of inflow and outflow cannulas and a magnetically levitated and driven centrifugal pump. Hemodynamic improvement was observed within 1 hour. Systemic vascular resistance decreased from 1413 +/- 453 to 1136 +/- 381 dyne (.) s (.) cm(-5) at 72 hours ( P = 0.0008). Pulmonary capillary wedge pressure decreased from 28.5 +/- 4.9 to 19.8 +/- 7.0 mm Hg ( P < 0.0001), and cardiac index ( excluding augmented aortic flow) increased from 1.97 +/- 0.44 to 2.27 +/- 0.43 L (.) min(-1) (.) m(-2) ( P = 0.0013). Serum creatinine trended downward during treatment ( overall P = 0.095). There were 8 complications during treatment, 7 of which were self-limited. Hemodynamics remained improved 24 hours after CAFA discontinuation. Conclusions - In patients with heart failure and persistent hemodynamic derangement despite intravenous inotropic and/or vasodilator therapy, CAFA improved hemodynamics, with a reduction in serum creatinine. CAFA represents a promising, novel mode of treatment for patients who are inadequately responsive to medical therapy. The clinical impact of the observed hemodynamic improvement is currently being explored in a prospective, randomized, controlled trial

Treating the Intestine with Oral ApoA-I Mimetic Tg6F Reduces Tumor Burden in Mouse Models of Metastatic Lung Cancer.

Having demonstrated that apolipoprotein A-I (apoA-I) mimetic peptides ameliorate cancer in mouse models, we sought to determine the mechanism for the anti-tumorigenic function of these peptides. CT-26 cells (colon cancer cells that implant and grow into tumors in the lungs) were injected into wild-type BALB/c mice. The day after injection, mice were either continued on chow or switched to chow containing 0.06% of a concentrate of transgenic tomatoes expressing the apoA-I mimetic peptide 6F (Tg6F). After four weeks, the number of lung tumors was significantly lower in Tg6F-fed mice. Gene expression array analyses of jejunum and lung identified Notch pathway genes significantly upregulated, whereas osteopontin (Spp1) was significantly downregulated by Tg6F in both jejunum and lung. In jejunum, Tg6F increased protein levels for Notch1, Notch2, Dll1, and Dll4. In lung, Tg6F increased protein levels for Notch1 and Dll4 and decreased Spp1. Tg6F reduced oxidized phospholipid levels (E06 immunoreactivity) and reduced 25-hydroxycholesterol (25-OHC) levels, which are known to inhibit Notch1 and induce Spp1, respectively. Notch pathway promotes anti-tumorigenic patrolling monocytes, while Spp1 facilitates pro-tumorigenic myeloid derived suppressor cells (MDSCs) formation. Tg6F-fed mice had higher numbers of patrolling monocytes in jejunum and in lung (p &lt; 0.02), and lower plasma levels of Spp1 with reduced numbers of MDSCs in jejunum and in lung (p &lt; 0.03). We conclude that Tg6F alters levels of specific oxidized lipids and 25-OHC to modulate Notch pathways and Spp1, which alter small intestine immune cells, leading to similar changes in lung that reduce tumor burden