BACKGROUND:As benefits of revascularization in non-ST elevation acute coronary syndromes (NSTEACSs) in the elderly are still unproven, we sought to assess the association between invasive or conservative management of NSTEACS and short-, mid- and long-term mortality or composite outcome of all-cause mortality and myocardial infarction in a cohort of consecutive elderly patients. METHODS AND RESULTS:Consecutive NSTEACS patients older than 75 years discharged between 2006 and 2010 from a single intensive cardiac care unit, and managed with invasive or conservative strategy according to available guidelines were retrospectively surveyed. By multivariate regression and sensitivity analysis, crude and adjusted mortality and composite outcome were estimated at prespecified time points of short-term (in-hospital or 30 days mortality), mid-term (T1: 31 days to 6 months), and long-term (T2: 31 days to 12 months). A total of 453 patients (median age 80 years, 47% men) were evaluated; 301 (66.5%) underwent invasive treatment. Invasive was associated with significantly lower risk of short- [odds ratio (OR) 0.28, 95% confidence interval (CI) 0.12-0.67, P = 0.004], mid- (OR 0.33, 95% CI 0.16-0.67, P = 0.003) and long-term mortality (OR 0.34, 95% CI 0.20-0.58, P < .0001). Invasive strategy was also associated with nonsignificant lower short- (OR 0.55, 95% CI 0.28-1.07, P = 0.077), and highly significant lower mid- (OR 0.52, 95% CI 0.34-0.81, P = 0.003) and long-term adjusted cumulative composite outcome rate (OR 0.68, 95% CI 0.46-0.98, P = 0.004). CONCLUSION:In NSTEACS elderly patients, invasive strategy is independently associated with lower short-, mid- and long-term mortality and composite outcome.

Background Inconsistent findings are reported on whether insulin-like growth factor-1 (IGF-1) is protective or harmful in predicting hypertension, carotid wall thickness and mortality. We determined the five-year prognostic value of IGF-1 for these outcomes in a large Black population prone to hypertension and cardiovascular disease. Design A longitudinal study as part of the PURE (Prospective Urban and Rural Epidemiology) study, North West Province, South Africa. Methods We measured IGF-1 and IGF binding protein-3 (IGFBP-3) in 1038 HIV-uninfected participants (age range 32–94 years) and assessed blood pressure, carotid intima-media thickness and mortality. Results Over five years 116 deaths occurred. Baseline IGF-1 was similar in survivors and non-survivors (p = 0.50), but tended to be higher in survivors upon adjustment for IGFBP-3 and covariates (p = 0.061). Normotensives and hypertensives (p = 0.072), and those with carotid intima-media thickness < 0.9 mm and ≥ 0.9 mm also displayed similar baseline IGF-1 (p = 0.55). Multivariable-adjusted Cox-regression indicated high IGF-1 predicting lower risk for all-cause mortality (hazard ratio 0.45; 0.23–0.88) and cardiovascular mortality (hazard ratio 0.26; 0.08–0.83) when also adjusting for IGFBP-3. When including normo- and hypertensives at baseline, high IGF-1 was related to normotension at follow-up (hazard ratio 0.68; 0.49–0.95). We found no association with carotid intima-media thickness (hazard ratio 0.59; 0.31–1.14). Conclusion In a Black South African population with low socio-economic status and harmful health behaviours, we found a protective independent association between IGF-1 and hypertension, cardiovascular and all-cause mortality, with no association with carotid wall thickness.

AIMSPatients with acute coronary syndromes (ACSs) who are managed without coronary revascularization represent a mixed and understudied population that seems to receive suboptimal pharmacological treatment.METHODS AND RESULTSWe assessed patterns of antithrombotic therapies employed during the hospitalization and in-hospital clinical events of medically managed patients with ACS enrolled in the prospective, multicentre, nationwide EYESHOT (EmploYEd antithrombotic therapies in patients with acute coronary Syndromes HOspitalized in iTalian cardiac care units) registry. Among the 2585 consecutive ACS patients enrolled in EYESHOT, 783 (30.3%) did not receive any revascularization during hospital admission. Of these, 478 (61.0%) underwent coronary angiography (CA), whereas 305 (39.0%) did not. The median GRACE and CRUSADE risk scores were significantly higher among patients who did not undergo CA compared with those who did (180 vs. 145, P < 0.0001 and 50 vs. 33, P < 0.0001, respectively). Antithrombotic therapies employed during hospitalization significantly differ between patients who received CA and those who did not with unfractioned heparin and novel P2Y12 inhibitors more frequently used in the first group, and low-molecular-weight heparins and clopidogrel in the latter group. During the index hospitalization, patients who did not receive CA presented a higher incidence of ischaemic cerebrovascular events and of mortality compared with those who underwent CA (1.6 vs. 0.2%, P = 0.04 and 7.9 vs. 2.7%, P = 0.0009, respectively).CONCLUSIONAlmost one-third of ACS patients are managed without revascularization during the index hospitalization. In this population, a lower use of recommended antiplatelet therapy and worse clinical outcome were observed in those who did not undergo CA when compared with those who did.CLINICAL TRIAL REGISTRATIONUnique identifier: NCT02015624, http://www.clinicaltrials.gov.

Conflicting evidence exists on the relationship between blood pressure (BP) and insulin-like growth factor-1 (IGF-1). We reviewed available articles and pooled extrapolated regression coefficients for the association between BP and total IGF-1 as reported in the literature and included additional data from 912 individuals from the general population. We identified 20 studies including 11 704 subjects. We also measured total IGF-1, insulin-like binding protein-3, and BP in 912 black and white men and women from South Africa (aged 20-70 years). When plotting positive and negative weighed regression coefficients (29 data points) against IGF-1, we found a significant positive relationship (r=0.31; P<0.001; n=11 704) intercepting the 0 point at 191 ng/mL IGF-1, suggesting an inverse BP/IGF-1 relationship in low IGF-1 conditions, and a positive relationship in overtly high IGF-1 conditions. In conclusion, our findings suggest that the relationship between BP and IGF-1 is dependent on, or related to, IGF-1 concentrations, as an expression of direct or reverse causality. Low IGF-1 bioavailability (associated with aging and vascular deterioration), resistance to IGF-1, and the complex interplay between IGF-1 and other vasoactive hormones could mask the vasoprotective functions of IGF-1 in cross-sectional studies or could modify their functions in prospective studies.

Background: Several new antithrombotic therapies have emerged for the treatment of acute coronary syndrome (ACS). We sought to assess contemporary patterns of antithrombotic therapies use in patients with ACS. Methods and results: EYESHOT (EmploYEd antithrombotic therapies in patients with acute coronary Syndromes HOspitalized in iTalian cardiac care units) was a nationwide, prospective registry aimed to evaluate antithrombotic strategies employed in patients admitted to intensive cardiac care units (CCUs) for an ACS in Italy. Over a three-week period, 203 CCUs enrolled 2585 consecutive patients: 41.2% with ST-elevation myocardial infarction (STEMI) and 58.8% with non-ST elevation ACS (NSTE-ACS). During hospitalisation, low-molecular-weight heparins, aspirin, and clopidogrel were the most commonly used antithrombotic therapies. Among patients treated with percutaneous coronary intervention (PCI, n=1755), any crossover of heparin therapy occurred in 30.8% of cases, while switching from one P2Y12 inhibitor to another occurred in 3.6% of cases in the CathLab and in 14.2% before discharge. Of the 790 patients who did not receive revascularisation, switching of a P2Y12 inhibitor occurred in 5.7% of cases. At discharge, a new P2Y12 inhibitor (ticagrelor or prasugrel) in association with aspirin was prescribed in 59.5% of STEMI and 33.9% of NSTE-ACS patients: the most powerful predictor for prescription was PCI (odds ratio (OR) 6.18; 95% confidence interval (CI) 4.76–8.01; p<0.0001), whereas age ≥75 years was strongly associated with clopidogrel use (OR 0.28; 95% CI 0.22–0.36; p<0.0001). Conclusions: The EYESHOT registry shows the current pattern of antithrombotic treatments for ACS patients admitted to Italian CCUs and provides insights which may help to improve the clinical care of such patients.

Hypertension in pregnancy is a major cause of maternal, fetal and neonatal morbidity and mortality, both in developing and developed countries. That is because it is the most common pathological condition during pregnancy and its development is associated with high risk of severe complications: mother could be affected by placental abruption, cerebrovascular events, organ dysfunction and could develop disseminated intravascular coagulation, instead the foetus could be affected by intrauterine growth retardation, premature birth and intrauterine death. Aware that preeclampsia still remains an enigma for different aspects, this review aims to provide a comprehensive update of all the current literature regarding this disease. In particular, the main purpose of this review is to emphasize the most recent findings about the pathophysiology, diagnosis and submit a revision of the most recent guidelines in relation to drug therapy, with particular attention to the evaluation of risks and benefits associated with the use of various classes of the currently available drugs.

Objectives: Insulin-like growth factor-1 (IGF-1) has potent endothelial-protective, anti-platelet and anti-thrombotic activities, and also exerts mitogenic and proliferatory actions on vascular smooth muscle cells. Conflicting reports exist regarding the role of IGF-1 in vascular protection and atherogenesis. We therefore investigated the relationships of ambulatory blood pressure (BP) and carotid intima-media thickness (cIMT) with a range of components of the IGF-1 axis in a bi-ethnic population.Methods: We included black (N = 86) and white (N = 101) men and measured growth hormone, total IGF-1, insulin-like growth factor binding protein-3 (IGFBP-3), and pregnancy-associated plasma proteinA (PAPP-A) levels.Results: Ambulatory BP was almost 10 mmHg higher in black men (137/88 mmHg versus 128/80 mmHg; both p < 0.001), accompanied by an adverse profile of the IGF-axis for all measured components (all p < 0.01), including reduced bioavailable IGF-1 (IGF-1/IGFBP-3; p = 0.006) and tissue IGF-1 accessibility index as represented by IGF-1. PAPP-A/IGFBP-3 (p < 0.001). Single, partial and multiple regression analyses confirmed an independent inverse association between ambulatory systolic BP and bioavailable IGF-1 in black men (R-2 = 0.24; beta = -0.22; p = 0.035). cIMT was similar in the ethnic groups (p = 0.34), and was negatively associated with bioavailable IGF-1 in white men (R-2 = 0.42; beta =-0.17; p = 0.039) prior to adjustment for gamma-glutamyl transferase (R-2 = 0.45; beta = -0.10; p = 0.25).Conclusion: Ambulatory systolic BP is inversely related to bioavailable IGF-1 in black men who displayed low IGF-1 concentrations. An inverse relation was found between cIMT and IGF-1 in white men, which disappeared after correction for g-glutamyl transferase - opposing reports of a detrimental role of IGF-1 in the early stages of atherogenesis. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

Background: Consistent benefit of invasive strategy (IS) in the management of myocardial infarction (MI) in elderly patients is not yet reported. Objectives: In non ST elevation acute coronary syndromes (NSTEACS) admitted within 48h of symptom onset, we aimed to determine in-hospital and 30-days mortality, and proportion of patients alive at 31 days to 6 months (T1) and 31 days to 12 months follow-up (T2). Cumulative rate of composite outcome (CO) of death/nonfatal MI/unstable angina was also analysed at 30 days, 6 and 12 months. Methods: A retrospective review of 453 consecutive patients > 75 yrs discharged after NSTEACS at a single ICCU between 2006 and 2010 was conducted. IS (n=301) or conservative strategy (CS) (n=152) were chosen as per medical judgment. Multivariate regression models to test the association between strategy and outcomes were used and a sensitivity analysis performed. Variables introduced into the models were age, gender, admission creatinine clearance, ejection fraction, haemoglobin and Killip classes, admission heart rate, blood pressure and cardiac arrest, ST deviation, peak troponin level, time from admission to percutaneous coronary intervenion (PCI), albumin serum levels. Results: Inhospital, 8 (2.7%) and 14 (9.2%), at 30 days, 11 (3,7%) and 21 (13,8%), at T1 28 (9,3%) and 44 (29,0%), and at T2 40 (13,3%) and 57 (37.5%), patients died in the IS and CS group respectively. At 30 days 25 (8,3%) and 24 (15,8%), at T1 52 (17,3%) and 56 (36,8%), and at T2 74 (24,6%) and 64 (42.1%), patients achieved the cumulative CO in the IS and CS group respectively. IS sizeably decreased adjusted in-hospital (OR 0.37, 95% CI 0.13-1.04, p=0.0603), 30-days (OR 0.28, 95% CI 0.12-0.67, p=0.004), T1 (T1 OR 0.33, 95% CI 0.16-0.67, p=0.0025) and T2 mortality (T2 OR 0.34, 95% CI 0.20-0.58, p=0.0001). IS correspondingly lowered cumulative rate of CO at 30 days (OR 0.55, 95% CI 0.28-1.07, p = 0.077), 6 months (OR 0.52, 95% CI 0.34-0.81, p = 0.003) and 12 months (OR 0.68, 95% CI 0.46-0.98, p = 0.0041). Further independent predictors of prognosis were also hemodynamic status (Killip class II-IV), or cardiac arrest at admission. Conclusions: IS was independently associated with a three-fold lower mortality and twofold lower CO in this high risk population at either brief, mid or long-term.

Preeclampsia is the major cause of maternofetal and neonatal morbi-mortality including intrauterine growth retardation, miscarriages and stillbirths. Inadequate vascular dilation and angiogenesis represent the crucial underlying defect of gravidic hypertension, denoting a failed response to the vasodilatory and pro-angiogenic challenge imposed by pregnancy, especially if multifetal. A similar pathogenesis appears involved in gestational diabetes. In this review we aimed to provide a hint on understanding the deeply involved angiogenic disorders which eventually culminate in utero-placental failure. The key players in these complex processes may be found in an intricate network of growth factors (GFs) and GF inhibitors, controlled by several vascular risk factors modulated by environment and genes, which eventually impact on early and late cardiovascular outcomes of mother and fetus.

Discovered as the primary regulator of erythropoiesis, erythropoietin (EPO) is involved in a broad variety of processes that play a major role in cardiovascular diseases. In particular, the antiapoptotic and pro-angiogenic properties of EPO have prompted a growing interest in the use of EPO for the treatment of myocardial infarction and heart failure. In a variety of myocardial ischemic injury animal models, EPO administration has been shown to acutely reduce infarct size, thereby preserving ventricular function. In addition, cardiac long-term effects of EPO, such as prevention of ventricular remodeling and heart failure, have been described. In recent years, several trials have tested the effects of recombinant human erythropoietin (rhEPO) administration in patients with myocardial infarction and chronic heart failure, in the attempt to translate the cardioprotection found in experimental models to human patients. In view of the generally controversial findings, in this updated review we provide an overview of the results of the most recent trials that investigated the role of erythropoiesis-stimulating agents (ESAs), including rhEPO and its analogue darbepoetin, in the treatment of acute myocardial infarction and heart failure. The problems related to safety and tolerability of ESA therapy are also discussed. Our analysis of the available literature demonstrates that the results of clinical studies in patients with cardiac disease are not uniform and the conclusions are contradictory. Further larger prospective studies are required to test clinical efficacy and safety of EPO.

Conflicting reports exist on the relationship between systolic BP (SBP) and insulin-like growth factor-1 (IGF-1). Where positive associations are observed in patients with acromegaly, others find a negative association or no relationship. The versatile functions of IGF-1 as a growth factor (vasoprotective versus arterial and cardiac remodelling), the interplay with other hormones as well as IGF-1 resistance phenomena as those shown in chronic renal failure, are mostly regarded as confounding this relationship and thereby resulting in conflicting results. We aimed to review and compare regression coefficients for the association between SBP and total IGF-1 as reported in the literature and two studies from the general population. We searched the literature for studies reporting the mentioned regression coefficients. We also included data from the SAfrEIC and SABPA studies in South Africa (total N=912) including African and Caucasian men and women, aged 20-70 yrs. When plotting the regression coefficients from 13 studies with 20 data points against IGF-1 concentrations, we found a significant association between the regression coefficients and IGF-1 concentration (r=0.80; p<0.001). The slope intercepted the y-axis at IGF-1 concentration of 223.5 ± 14.4 ng/mL. Studies with mean IGF-1 at this range reported weak non-significant regression coefficients (typically young healthy men). Studies including acromegalic patients or adolescents reported significant positive associations, with negative associations for those with compromised cardiovascular function. Our findings suggest that the regression coefficient for the SBP and IGF-1 relationship is dependent on the IGF-1 concentration. Positive associations are observed in situations with overtly high IGF-1 concentrations as those found in acromegaly or conditions of IGF-1 resistance, and beneficial negative relationships seen in those with low-normal IGF-1 and with compromised vascular function such as type 2 diabetes and hypertension. Our results suggest that the complex interplay between IGF-1 and other vasoactive hormones (e.g. growth hormone, insulin, cortisol and adipokines) or the development of a vascular resistance to IGF-1, may hamper the vasoprotective functions of IGF-1.

We aimed to revise the increasingly accruing data about the association between anti-tyrosinkinase, “targeted” cancer drugs and the development of arterial thrombotic events or acute coronary syndromes. Further insights into the involved pathophysiologic mechanisms, and into the clinical implications are overviewed.Antiangiogenesis has become a mainstream of cancer therapy, leading to development of a specific class of drugs. Besides, a “wider” angiogenesis network made up of several growth factors, can be recognized as target of a higher number of compounds. Their widespread use has been progressively favored over conventional chemotherapy, because of their better safety/efficacy profile, even allowing a prolonged administration. However, there is a growing awareness of an association between these useful drugs and serious cardiovascular side effects including myocardial infarction, stroke, heart failure and cardiovascular death, in addition to the known relation with the most frequent hypertension onset. Observational studies indeed report that combined cardiovascular events may reach figures of 20–40%, and, for their management, several monitoring, diagnostic and therapeutic regimens have been suggested.On the basis of the available data we recommend an active screening program for acute coronary syndromes in the “at risk” period, immediately after the beginning of the “targeted” drug therapy, and during the whole administration time. Likewise, a mandatory cardiological specialistic evaluation is warranted to plan a schedule of follow-up evaluations for diagnostics, including ECG, echocardiogram, and multimarker evaluation. An appropriate treatment with antiplatelet or anticoagulant drugs, endothelial protective agents or cardiovascular interventions is similarly advised.

Even though cancer therapies attain nowadays as many as 10 million survivors, some studies surprisingly report a higher risk of cardiovascular death compared with that of tumor recurrence. Cancer survivors are thus candidates for a thorough cardiovascular evaluation, because they acquire cardiovascular risk together with oncologic cure. VEGF or tyrosinkinase inhibitors, increasingly used in a large variety of tumours with a significant survival advantage, are prototypical drugs simultaneously realizing oncologic care and cardiotoxicity, by targeting angiogenic replicative pathways, involved in both cardiac health and cancer progression. The pathophysiology of cardiovascular disease, mainly consisting in defective angiogenesis, is indeed opposite to that of tumorigenesis and metastasis spreading, both crucially sustained by enhanced blood vessel development. The clinical expression of cardiotoxicity includes not only the development of a dilated hypokinetic cardiomyopathy, currently generally treated with cardiological drugs, but also hypertension, clinical or subclinical atherothrombotic ischemic heart disease and ischemic cardiomyopathy. These clinical syndromes deserve a more adequate cardiovascular assessment and appropriate advanced treatment strategies including percutaneous coronary intervention, coronary artery bypass graft, or device implantation. If not proactively suspected, diagnosed and treated, these manifestations may lead to cardiac events, and reduce overall survival.This review analyzes the available evidence about molecular pathways, predictors and monitoring of impaired angiogenesis-driven cardiotoxicity. Even clinical relevance, pharmacodynamics and markers of efficacy of various intended or "accidental" antiangiogenic drugs will be discussed with the purpose of easing appropriate cardiological surveillance and treatment. Drug tailoring aimed at outcome and cost-effectiveness, according to both drug susceptibility and cardiovascular vulnerability will be finally revised.

IGF-1 (insulin-like growth factor-1) plays a unique role in the cell protection of multiple systems, where its fine-tuned signal transduction helps to preserve tissues from hypoxia, ischaemia and oxidative stress, thus mediating functional homoeostatic adjustments. In contrast, its deprivation results in apoptosis and dysfunction. Many prospective epidemiological surveys have associated low IGF-1 levels with late mortality, MI (myocardial infarction), HF (heart failure) and diabetes. Interventional studies suggest that IGF-1 has anti-atherogenic actions, owing to its multifaceted impact on cardiovascular risk factors and diseases. The metabolic ability of IGF-1 in coupling vasodilation with improved function plays a key role in these actions. The endothelial-protective, anti-platelet and anti-thrombotic activities of IGF-1 exert critical effects in preventing both vascular damage and mechanisms that lead to unstable coronary plaques and syndromes. The pro-survival and anti-inflammatory short-term properties of IGF-1 appear to reduce infarct size and improve LV (left ventricular) remodelling after MI. An immune-modulatory ability, which is able to suppress 'friendly fire' and autoreactivity, is a proposed important additional mechanism explaining the anti-thrombotic and anti-remodelling activities of IGF-1. The concern of cancer risk raised by long-term therapy with IGF-1, however, deserves further study. In the present review, we discuss the large body of published evidence and review data on rhIGF-1 (recombinant human IGF-1) administration in cardiovascular disease and diabetes, with a focus on dosage and safety issues. Perhaps the time has come for the regenerative properties of IGF-1 to be assessed as a new pharmacological tool in cardiovascular medicine.

EPO (erythropoietin) has long been identified as a primary regulator of erythropoiesis. Subsequently, EPO has been recognized as playing a role in a broad variety of processes in cardiovascular pathophysiology. In particular, the tight interactions of EPO with the nitric oxide pathway, apoptosis, ischaemia, cell proliferation and platelet activation appear of great interest. Although enhanced EPO synthesis is viewed as an appropriate compensatory mechanism in the cardio renal syndrome, which features CHF (congestive heart failure) and CRF (chronic renal failure), maladaptative excessive EPO synthesis in the advanced stages of these diseases appears to be predictive of higher mortality. Clinical trials based on the use of EPO in both heart and renal failure have so far produced contradictory results, whereas treatment targeted to restore low Hb levels appears rational and is supported by regulatory authorities. New areas for therapeutic use of EPO, such as acute coronary syndromes, are under investigation, and they are discussed in the present review together with other clinical applications in cardiovascular diseases. The revisited concept of a potential use of endogenous EPO levels as a predictor of CHF severity, as well as in the monitoring of responses to treatment, deserves appropriate investigation, as this may identify EPO as a useful biomarker in the clinical management of cardiovascular diseases.