Circulating soluble fibroblast activation protein (FAP) levels are independent of cardiac and extra-cardiac FAP expression determined by targeted molecular imaging in patients with myocardial FAP activation.

INTRODUCTION: Tissue Fibroblast Activation Protein alpha (FAP) is overexpressed in various types of acute and chronic cardiovascular disease. A soluble form of FAP has been detected in human plasma, and low circulating FAP concentrations are associated with increased risk of death in patients with acute coronary syndrome. However, little is known about the regulation and release of FAP from fibroblasts, and whether circulating FAP concentration is associated with tissue FAP expression. This study characterizes the release of FAP in human cardiac fibroblasts (CF) and analyzes the association of circulating FAP concentrations with in vivo tissue FAP expression in patients with acute (ST-segment elevation myocardial infarction, STEMI) and chronic (severe aortic stenosis, AS) myocardial FAP expression. METHODS AND RESULTS: FAP was released from CF in a time- and concentration-dependent manner. FAP concentration was higher in supernatant of TGFß-stimulated CF, and correlated with cellular FAP concentration. Inhibition of metallo- and serine-proteases diminished FAP release in vitro. Median FAP concentrations of patients with acute (77 ng/mL) and chronic (75 ng/mL, p = 0.50 vs. STEMI) myocardial FAP expression did not correlate with myocardial nor extra-myocardial nor total FAP volume (P ≥ 0.61 in all cases) measured by whole-body FAP-targeted positron emission tomography. CONCLUSION: We describe a time- and concentration dependent, protease-mediated release of FAP from cardiac fibroblasts. Circulating FAP concentrations were not associated with increased in vivo tissue FAP expression determined by molecular imaging in patients with both chronic and acute myocardial FAP expression. These data suggest that circulating FAP and tissue FAP expression provide complementary, non-interchangeable information.

Creatine Phosphate Administration in Cell Energy Impairment Conditions: A Summary of Past and Present Research.

BACKGROUND: Creatine phosphate (CrP) plays a fundamental physiological role by providing chemical energy for cell viability and activity, especially in muscle tissue. Numerous pathological conditions, caused by acute or chronic ischaemic situations, are related to its deficiency. For these reasons, it has been used as a cardioprotective agent in heart surgery and medical cardiology for many years. OBJECTIVE: This article gives a brief overview of the main characteristics of exogenous CrP. METHODS: Previous review articles on CrP were screened for relevant information and references. Results from selected studies were reviewed and classified according to the topics in this review article and provided further interesting information on the pharmacological role of this molecule. RESULTS: Besides CrP's well known cell energy and function restoring properties, new evidence is emerging regarding its antioxidant and anti-apoptotic properties. Use of CrP is well established clinically as an intraoperative and perioperative adjuvant in heart operations (valve replacement, coronary artery bypass grafting, congenital heart defect repair), and as an additional agent in medical cardiology therapy for acute myocardial infarction and acute and chronic heart failure. In particular, there are promising potential new CrP uses in neurology, such as in cerebral ischaemia and hypoxic ischaemic encephalopathy. CONCLUSIONS: This review article describes the role of CrP treatment in cardiological indications, such as cardioprotection in cardioplegia and in myocardiopathies of various etiopathogenesis, as well as in other clinical indications such as skeletal muscle rehabilitation and neurological conditions.

Mineralocorticoid receptor antagonism and cardiac remodeling in ischemic heart failure.

Aldosterone production in the heart as well as aldosterone plasma levels are increased after myocardial infarction and in congestive heart failure, correlating with the severity of disease. Aldosterone promotes sodium and water retention, sympathoadrenergic activation, endothelial dysfunction, and cardiovascular fibrosis and hypertrophy. Even maximally recommended doses of ACE inhibitors do not completely prevent formation of aldosterone. The Randomized Aldactone Evaluation Study (RALES) and the Eplerenone Post acute myocardial infarction Heart failure Efficacy and SUrvival Study (EPHESUS) demonstrated that aldosterone receptor blockade markedly reduces mortality among patients with heart failure. This review summarizes recent clinical and experimental data on the effect of aldosterone antagonists on left ventricular remodeling and function in ischemic heart failure with special emphasis on potential underlying mechanisms. While reduction of excessive extracellular matrix turnover leading to decreased fibrosis appears to be the most important effect of mineralocorticoid receptor antagonism in heart failure, other mechanisms such as regression of hypertrophy, improvement of endothelial function, reduction of superoxide formation, and enhanced renal sodium excretion may contribute. Recent data showed that in rats with left ventricular dysfunction after extensive myocardial infarction, eplerenone on top of ACE inhibition more effectively improved cardiac remodeling and molecular alterations than ACE inhibition alone.

Improvement of left ventricular remodeling and function by hydroxymethylglutaryl coenzyme a reductase inhibition with cerivastatin in rats with heart failure after myocardial infarction.

BACKGROUND: Hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) attenuate angiotensin II-induced cellular signaling. Because angiotensin II is involved in left ventricular (LV) remodeling after myocardial infarction (MI), we examined the effects of statin treatment in an experimental model of chronic heart failure after MI. METHODS AND RESULTS: Rats with extensive MI were treated with placebo or cerivastatin (0.3 mg/kg per day) as a dietary supplement or via gavage for 11 weeks starting on the 7th postoperative day. Infarct size and cholesterol levels were similar among all groups. LV cavity area, an index of LV dilatation, was reduced in MI rats on cerivastatin compared with placebo. LV end-diastolic pressure was increased in MI rats on placebo (24.1+/-4.1 mm Hg versus sham: 5.1+/-0.3 mm Hg; P<0.01), and it was significantly reduced by cerivastatin treatment (13.7+/-2.7 mm Hg; P<0.05 versus placebo). Cerivastatin partially normalized LV dP/dt(max) and dP/dt(min), indices of LV systolic and diastolic function, which were significantly reduced in MI rats on placebo. Improvement of LV function by cerivastatin was accompanied by a reduced expression of collagen type I and beta-myosin heavy chain. LV endothelial nitric oxide synthase was increased, whereas the nitrotyrosine protein level was decreased in MI rats by cerivastatin treatment. CONCLUSIONS: Cerivastatin improved LV remodeling and function in rats with heart failure. This effect was associated with an attenuated LV expression of fetal myosin heavy chain isoenzymes and collagen I. Statin treatment may retard the progression of chronic heart failure.

Fast high-resolution magnetic resonance imaging demonstrates fractality of myocardial perfusion in microscopic dimensions.

The fractal nature of heterogeneity of myocardial blood flow and its implications for the healthy and diseased heart is not yet understood. The main hindrance for investigation of blood flow heterogeneity and its role in physiology and pathophysiology is that conventional methods for determination of myocardial perfusion have severe limitations concerning temporal and spatial resolution and invasiveness. In isolated rat hearts, we developed a nuclear magnetic resonance technique that does not depend on contrast agents and in which the apparent longitudinal relaxation time is made perfusion sensitive by selective preparation of the imaging slice. This perfusion-sensitive relaxation time is determined within 40 seconds as a map with a high spatial in-plane resolution of 140x140 microm(2) and a thickness of 1.5 mm. Perfusion imaging was validated with the established microsphere technique. Additionally, the congruence between perfusion-sensitive T:(1) maps and first-pass perfusion imaging was demonstrated. As an application of high-resolution perfusion imaging, fractal analysis of the spatial distribution of perfusion was performed. We were able to demonstrate that the fractality of this distribution exists even in microscopic dimensions. Vasodilation by nitroglycerin modulated the fractal pattern of perfusion, and the decrease of the fractal dimension indicated a shift toward homogeneity. This implies that parameters of the fractal distribution depend on the microvascular tone rather than on anatomic preformations; ie, fractality is a functional characteristic of perfusion.

Endothelin-receptor blockade improves endothelial vasomotor dysfunction in heart failure.

OBJECTIVES: To elucidate the effect of selective endothelin ET(A)- and mixed ET(A/B)-receptor antagonists on endothelial vasomotor dysfunction in rats with heart failure after myocardial infarction (MI). METHODS: Vasoreactivity and superoxide anion formation were determined in aortic rings from Wistar rats 12 weeks after extensive MI (>46% of left ventricle) compared to sham-operated animals. Rats were either treated with the selective ET(A)-receptor antagonist LU 135252 (30 mg/kg/day), the mixed ET(A/B)-receptor antagonist Bosentan (100 mg/kg/day) or placebo. RESULTS: In MI rats, the concentration-response curve of the endothelium-dependent, nitric oxide-mediated relaxation induced by acetylcholine was significantly shifted to the right and the maximum relaxation was attenuated. Long-term treatment with both ET antagonists significantly improved acetylcholine-induced relaxation in MI rats. LU 135252 was more effective than Bosentan. Endothelium-independent relaxations induced by sodium nitroprusside as well as endothelin- and phenylephrine-induced contractions were similar in all groups of rats. Plasma renin activity and aortic superoxide formation, which were enhanced in rats with heart failure, were normalized by LU 135252, but not by Bosentan treatment. CONCLUSIONS: Long-term treatment with ET-receptor antagonists improves endothelial vasomotor dysfunction in rats with chronic MI. This mechanism may essentially contribute to the beneficial effects of ET receptor blockade in heart failure.

Chronic endothelin receptor blockade attenuates progressive ventricular dilation and improves cardiac function in rats with myocardial infarction: possible involvement of myocardial endothelin system in ventricular remodeling.

BACKGROUND: Left ventricular dilatation after myocardial infarction is associated with impaired ventricular function and heart failure and has important implications for survival. The purpose of this study was to investigate the role of endothelin-1 (ET-1) in ventricular dilatation and the effects of chronic endothelin receptor blockade by a mixed ET(A) and ET(B) receptor blocker (bosentan) on the circulating and cardiac endothelin systems. METHODS AND RESULTS: Three hours after coronary ligation or sham operation, bosentan (100 mg x kg body wt(-1) x d(-1)) or placebo was given by gavage. Seven days and 8 weeks after surgery, hemodynamic and left ventricular volume studies were performed. Acute bosentan treatment (7 days) had no effects on hemodynamic parameters and early left ventricular dilatation. In the rats with large infarcts, chronic bosentan treatment (8 weeks) versus placebo reduced left ventricular systolic pressure (116+/-2 versus 125+/-3 mm Hg, P<.05) and arterial pressure (93+/-2 versus 103+/-3 mm Hg, P<.05), improved stroke volume index (0.69+/-0.06 versus 0.52+/-0.04 mL/kg, P<.05), and prevented in part the rightward shift of the pressure-volume curve. Chronic bosentan treatment also decreased ET-1 levels (390+/-33 versus 475+/-22 pg/g tissue, P<.05) and density of ET-1 receptors (262+/-24 versus 346+/-31 fmol/mg protein, P<.05) in left ventricular myocardium. CONCLUSIONS: In the present study, a mixed ET(A) and ET(B) receptor antagonist (bosentan) partially prevented left ventricular dilatation and improved hemodynamics, suggesting that endothelin plays a role in left ventricular remodeling after myocardial infarction. Supporting this hypothesis, we show inhibitory effects of bosentan on the peripheral and myocardial endothelin system.

Different rates of forearm bone loss in healthy women with early or late menopause.

The aim of this study was to evaluate whether healthy women with early or late menopause have different rates of age- and menopause-related bone loss, and whether premature menopause really represents a risk factor for osteopenia. Healthy women aged from 27 to 84 years (n = 2204), with no history of fractures, were divided into two groups according to their age at menopause (AAM): group A with AAM < or = 43, and group B with AAM > or = 50 years. Bone mineral density (BMD) was measured in the distal non-dominant forearm by single-photon absorptiometry. Group B had a significantly lower average BMD than group A (group A, 0.430 +/- 0.074 g/cm2; group B, 0.419 +/- 0.081; p = 0.003); however, the average age of group A was significantly lower, and weight and height were significantly higher. When women older than 50 years of age were divided into five age-matched subgroups, BMD was significantly lower in women with AAM < or = 43 years up to 60 years; after that age this difference disappeared and, in the oldest subgroups, BMD was significantly lower in group B than in group A. Independent variables such as age, AAM and body mass index (BMI) explain about 30% of the variation of BMD, using a multiple linear regression analysis. In both groups age and BMI weighted more than AAM in determining BMD. When BMD was plotted versus either chronological age or years since menopause, women with late menopause showed a significantly faster bone loss than those with early menopause.(ABSTRACT TRUNCATED AT 250 WORDS)

Bone mass and mineral metabolism in Klinefelter's syndrome.

A reduced bone mineral density (BMD) is frequently observed in hypogonadal males; however, very little is known on bone and mineral metabolism in Klinefelter's syndrome (KS). In this study 32 XXY KS patients and 24 healthy age-matched male controls were examined. Serum total and free testosterone (TT and FT) were significantly lower in patients than in controls (TT in KS, 15.1 +/- 7.8 nmol/l; controls, 30.4 +/- 9.1; p < 0.001. FT in KS, 81.8 +/- 24.9 pmol/l; controls, 135.7 +/- 16.4; p < 0.001). 17 beta-Estradiol was slightly higher in KS patients (KS, 49.0 +/- 27.1 pg/ml; controls, 39.3 +/- 16.4 pg/ml), but the difference was not significant. BMD, measured at the spine (L2-4) and at the proximal epiphysis of the left femur, was similar in patients and in the control group (spine: KS, 1.016 +/- 0.142; controls, 1.085 +/- 0.144 g/cm2; p = not significant. Femoral neck: KS, 0.926 +/- 0.149; controls, 0.926 +/- 0.122 g/cm2; p = not significant). Bone GLA protein (BGP) was significantly higher in the KS group (12.7 +/- 4.8 vs 8.9 +/- 5.2 ng/ml; p < 0.02), while serum calcium, serum phosphate, calciotrophic hormones and the fasting urinary hydroxyproline/creatinine ratio (OHP/Creat) were similar in the two groups. A positive relationship between FT and both spine and femoral BMD was found in KS patients. Furthermore, OHP/Creat ratio was inversely related to BMD at the femur, and positively related to BGP in KS patients, but not in normal subjects. These findings suggest that (1) KS patients have normal bone mass, most probably because the hypogonadism is moderate; and (2) patients with lower bone mass appear to have higher bone turnover.

Influence of aging and menopause in determining vertebral and distal forearm bone loss in adult healthy women.

In order to assess the relative influence of aging and menopause in determining the decrease of bone mass in adult women, two groups of normal subjects were examined in this retrospective, cross-sectional study. In group A, bone mineral density (BMD) was evaluated at spine (L2-L4) by dual X-ray absorptiometry (DXA) (Hologic QDR-1000); in group B, BMD was measured at the distal forearm by single photon absorptiometry (SPA) (Osteometer DT 100). Both groups were further divided into two subgroups: A1 and B1 included women with the same postmenopausal, but different chronological age; A2 and B2 included women with the same chronological, but different postmenopausal age. BMD and BMI-corrected BMD (cBMD) were plotted versus age and years since menopause, respectively. Mathematical analysis of the correlation curves between BMD and chronological age showed that the decrease of BMD is very similar at spine and forearm, and is better fitted by a quadratic function. Age-related fractional bone diminution shows a progressive increase with aging (at spine: -0.38%/year at 45 years, -0.81%/year at 50, -1.3%/year at 55 and -1.9%/year at 60. At forearm: -0.5%/year at 50 years, -1.1%/year at 55 and -1.68%/year at 60). On the other hand, menopause-related BMD decrement is very evident during the first year since menopause (at spine: -8.1%/year; at forearm: -3.4%/year), and progressively decreases, according to a logarithmic function. Ten years later, yearly diminution of BMD is below 1%/year and 0.4%/year at spine and forearm, respectively. At this time, age contributes to determine bone loss for 2/3 and menopause for 1/3.