Cancer in chronic heart failure patients in the GISSI-HF trial.

BACKGROUND: Cancer complicating heart failure (HF) is an emerging issue. We investigated it in the GISSI-HF trial, which uniquely included patients with malignancies if deemed likely to allow follow-up. METHODS AND RESULTS: At enrolment, 256 of 6913 participants in GISSI-HF (3.7%) had a tumour diagnosis, which was malignant (cancer) in 145 (2.1%). Patients with cancer were older and more often former smokers, had lower body mass index, lower left ventricular ejection fraction (LVEF), less implanted devices, lower glucose and haemoglobin and higher uric acid levels than those without cancer. During a median 4-year follow-up, cardiovascular (CV), non-CV non-cancer and cancer death occurred in 1477, 272 and 220 subjects (75%, 13.8% and 11.2% of total mortality, respectively). Cancer at trial entry portended an increased risk of all-cause mortality after accounting for age and confounders (HR 1.33, 95%CI 1.02-1.73), which was attributable to cancer-specific mortality. Among the 6657 patients without any tumour at enrolment, 1879 subsequently died. CV, non-CV non-cancer and cancer causes accounted for 1422 (75.7%), 261 (13.9%) and 196 (10.4%) of these deaths, respectively, median time to specific death being 22, 25 and 30 months (P < .0001). Patients facing cancer vs CV death had lower NYHA class, slower heart rate, higher blood pressure, higher LVEF, shorter HF history, less diuretic use, lower creatinine and uric acid and higher haemoglobin and cholesterol. CONCLUSIONS: Even when considered not aggressive, concomitant cancer worsens HF prognosis. The inverse relationship between HF severity and cancer death in the absence of prior tumour warrants further study.

Microgram amounts of abscisic acid in fruit extracts improve glucose tolerance and reduce insulinemia in rats and in humans.

2-Cis,4-trans-abscisic acid (ABA) is a plant hormone that is present also in animals. Several lines of evidence suggest that ABA contributes to the regulation of glycemia in mammals: nanomolar ABA stimulates insulin release from ß-pancreatic cells and glucose transporter-4-mediated glucose uptake by myoblasts and adipocytes in vitro; plasma ABA increases in normal human subjects, but not in diabetic patients, after a glucose load for an oral glucose tolerance test (OGTT). The presence of ABA in fruits prompted an exploration of the bioavailability of dietary ABA and the effect of ABA-rich fruit extracts on glucose tolerance. Rats underwent an OGTT, with or without 1 µg/kg ABA, either synthetic or present in a fruit extract. Human volunteers underwent an OGTT or a standard breakfast and lunch, with or without a fruit extract, yielding an ABA dose of 0.85 or 0.5 µg/kg, respectively. Plasma glucose, insulin, and ABA were measured at different time points. Oral ABA at 0.5-1 µg/kg significantly lowered glycemia and insulinemia in rats and in humans. Thus, the glycemia-lowering effect of low-dose ABA in vivo does not depend on an increased insulin release. Low-dose ABA intake may be proposed as an aid to improving glucose tolerance in patients with diabetes who are deficient in or resistant to insulin.

Vitamin D modulates the association of circulating insulin-like growth factor-1 with carotid artery intima-media thickness.

OBJECTIVE: Experimental evidence indicates that circulating insulin-like growth factor-1 (IGF-1) counteracts vascular aging and atherosclerosis, for which increased carotid artery intima-media thickness (IMT) is a marker. Yet, IGF-1 concentrations have been inconsistently associated with carotid IMT in epidemiological studies. Since vitamin D is also implicated in vascular protection and affects IGF-1 biology, we hypothesized that it would influence the effect of IGF-1 on IMT. METHODS: The relationship between carotid IMT and fasting serum IGF-1 was examined across strata of 25-hydroxyvitamin D [25(OH)D] in 472 participants in the Baltimore Longitudinal Study of Aging (BLSA) with well-controlled blood pressure and in 165 treatment-naive patients with essential hypertension from the Microalbuminuria: A Genoa Investigation on Complications (MAGIC) study. Moreover, the interplay between vitamin D and IGF-1 was preliminarily explored in EA.hy926 endothelial cells. RESULTS: After adjusting for age, sex, BMI, renal function, smoking, systolic blood pressure, LDL-cholesterol, glycemia, antihypertensive or lipid-lowering therapy, season, parathyroid hormone, and vitamin D supplementation, IGF-1 was significantly and negatively associated with carotid IMT only within the lowest 25(OH)D quartile (range 6.8-26 ng/mL) of the BLSA (ß -0.095, p = 0.03). Similarly, a significant negative correlation between IGF-1 and carotid IMT was found after full adjustment only in MAGIC patients with 25(OH)D concentrations below either the deficiency cut-off of 20 ng/mL (ß -0.214, p = 0.02) or 26 ng/mL (ß -0.174, p = 0.03). Vitamin D dose-dependently decreased hydrogen peroxide-induced endothelial cell oxidative stress and apoptosis, which were further inhibited by IGF in the presence of low, but not high vitamin D concentration. CONCLUSIONS: Circulating IGF-1 is vasoprotective primarily when vitamin D levels are low. Future studies should address the mechanisms of vitamin D/IGF-1 interaction.

Vitamin D increases circulating IGF1 in adults: potential implication for the treatment of GH deficiency.

OBJECTIVES: Previous studies suggested that vitamin D modulates circulating IGF1. We investigated this effect in adults and its clinical relevance in the management of GH deficiency (GHD). DESIGN AND METHODS: IGF1 levels were prospectively measured before and after 12 weeks of treatment with oral vitamin D3 (5000 or 7000 IU/week) vs no intervention in 39 subjects 61.9±7.9 years old. The frequency of IGF1 values ≥50th age- and sex-specific percentile in relation to vitamin D status, as determined by the concentration of 25-hydroxyvitamin D (25(OH)D), was retrospectively assessed in 69 GHD patients (57.4±16.6 years) on stable hormone replacement and with 25(OH)D and IGF1 concurrently measured. RESULTS: Treatment with 5000 and 7000 IU vitamin D3/week significantly raised 25(OH)D by 12.7±8.4 and 13.1±6.5 ng/ml respectively (both P<0.001 vs baseline). In the 7000 IU group, IGF1 levels also significantly increased by 31.3±36.7 ng/ml (P=0.01). Neither 25(OH)D nor IGF1 significantly varied in controls. IGF1 was ≥50th percentile more frequently in GHD patients with 25(OH)D levels ≥15 than <15 ng/ml (65.9 vs 40.0%, P<0.05). Logistic regression with adjustment for recombinant human GH (rhGH) dose, vitamin D supplements, gender, use of thyroid hormones, corticosteroids or estrogen/testosterone, and season revealed a significant positive association between ≥15 ng/ml 25(OH)D and IGF1 ≥50th percentile (OR 4.4, 95% CI 1.0-18.8, P<0.05). A significant negative correlation between 25(OH)D concentrations and rhGH dose was found after correcting for age and IGF1 (ß -0.042, P<0.01), but not after further adjusting for sex, thyroid, adrenal or gonadal replacement, and season (ß -0.037, P=0.06). CONCLUSIONS: Vitamin D increases circulating IGF1 in adults. As a result, a better vitamin D status may ease the achievement of normal IGF1 values in GHD.