Paolo Calabrò

Radial versus femoral access in patients with acute coronary syndromes undergoing invasive management: a randomised multicentre trial

BACKGROUND It is unclear whether radial compared with femoral access improves outcomes in unselected patients with acute coronary syndromes undergoing invasive management. METHODS We did a randomised, multicentre, superiority trial comparing transradial against transfemoral access in patients with acute coronary syndrome with or without ST-segment elevation myocardial infarction who were about to undergo coronary angiography and percutaneous coronary intervention. Patients were randomly allocated (1:1) to radial or femoral access with a web-based system. The randomisation sequence was computer generated, blocked, and stratified by use of ticagrelor or prasugrel, type of acute coronary syndrome (ST-segment elevation myocardial infarction, troponin positive or negative, non-ST-segment elevation acute coronary syndrome), and anticipated use of immediate percutaneous coronary intervention. Outcome assessors were masked to treatment allocation. The 30-day coprimary outcomes were major adverse cardiovascular events, defined as death, myocardial infarction, or stroke, and net adverse clinical events, defined as major adverse cardiovascular events or Bleeding Academic Research Consortium (BARC) major bleeding unrelated to coronary artery bypass graft surgery. The analysis was by intention to treat. The two-sided α was prespecified at 0·025. The trial is registered at ClinicalTrials.gov, number NCT01433627. FINDINGS We randomly assigned 8404 patients with acute coronary syndrome, with or without ST-segment elevation, to radial (4197) or femoral (4207) access for coronary angiography and percutaneous coronary intervention. 369 (8·8%) patients with radial access had major adverse cardiovascular events, compared with 429 (10·3%) patients with femoral access (rate ratio [RR] 0·85, 95% CI 0·74-0·99; p=0·0307), non-significant at α of 0·025. 410 (9·8%) patients with radial access had net adverse clinical events compared with 486 (11·7%) patients with femoral access (0·83, 95% CI 0·73-0·96; p=0·0092). The difference was driven by BARC major bleeding unrelated to coronary artery bypass graft surgery (1·6% vs 2·3%, RR 0·67, 95% CI 0·49-0·92; p=0·013) and all-cause mortality (1·6% vs 2·2%, RR 0·72, 95% CI 0·53-0·99; p=0·045). INTERPRETATION In patients with acute coronary syndrome undergoing invasive management, radial as compared with femoral access reduces net adverse clinical events, through a reduction in major bleeding and all-cause mortality. FUNDING The Medicines Company and Terumo.

Atrial Myocardial Deformation Properties Predict Maintenance of Sinus Rhythm After External Cardioversion of Recent-Onset Lone Atrial Fibrillation A Color Doppler Myocardial Imaging and Transthoracic and Transesophageal Echocardiographic Study

Background—Accurate echocardiographic parameters to predict maintenance of sinus rhythm in patients with atrial fibrillation (AF) are poorly defined. This study was conducted to assess the atrial myocardial properties during AF through myocardial velocity, strain rate, and strain and to compare their prognostic value in maintaining sinus rhythm in patients with lone AF with standard transthoracic (TTE) and transesophageal echocardiography (TEE). Methods and Results—Sixty-five consecutive patients with lone AF for ≤3 months underwent TTE, TEE, and myocardial velocity and strain and strain rate imaging examinations before successful external cardioversion. Maintenance of sinus rhythm was assessed during a 9-month follow-up. Atrial myocardial velocity, strain, and strain rate values in AF patients were compared with those of age- and sex-matched referents. Moreover, clinical and echocardiographic parameters of patients with maintenance of sinus rhythm (MSR patients) over the 9-month follow-up period (n=25) were compared with those from patients with AF recurrence (AFR patients; n=40). Atrial myocardial properties assessed by myocardial velocity, strain rate, and strain were significantly reduced (P<0.0001) in patients (velocity, 3.2±1.4 cm/s; strain, 23.3±19%; strain rate, 2±0.9 seconds−1) compared with referents (velocity, 5.7±1.3 cm/s; strain, 92±26%; strain rate, 4.2±1.8 seconds−1). The individual predictors of sinus rhythm maintenance were atrial appendage flow velocity (MSR patients, 39±12 cm/s; AFR patients, 32±15 cm/s; P<0.01) assessed by TEE and atrial strain (MSR patients, 33±27%; AFR patients, 17±9%; P=0.0007) and strain rate (MSR patients, 2.7±1 seconds−1; AFR patients, 1.6±0.6 seconds−1; P<0.0001) peak systolic values. Atrial strain (P<0.0001; coefficient, 0.015; SE, 0.003) and strain rate (P<0.0001; coefficient, 0.372; SE, 0.075) parameters alone were confirmed as independent predictors of sinus rhythm maintenance by multivariable analysis. Conclusions—Patients with higher atrial strain and strain rate appear to have a greater likelihood of staying in sinus rhythm. If the current data are verified in future studies, then additional pharmacological therapy and maintenance of anticoagulants for a longer period may need to be considered in those with lower atrial strain and strain rate measurements.

Bivalirudin or Unfractionated Heparin in Acute Coronary Syndromes

BACKGROUND Conflicting evidence exists on the efficacy and safety of bivalirudin administered as part of percutaneous coronary intervention (PCI) in patients with an acute coronary syndrome. METHODS We randomly assigned 7213 patients with an acute coronary syndrome for whom PCI was anticipated to receive either bivalirudin or unfractionated heparin. Patients in the bivalirudin group were subsequently randomly assigned to receive or not to receive a post-PCI bivalirudin infusion. Primary outcomes for the comparison between bivalirudin and heparin were the occurrence of major adverse cardiovascular events (a composite of death, myocardial infarction, or stroke) and net adverse clinical events (a composite of major bleeding or a major adverse cardiovascular event). The primary outcome for the comparison of a post-PCI bivalirudin infusion with no post-PCI infusion was a composite of urgent target-vessel revascularization, definite stent thrombosis, or net adverse clinical events. RESULTS The rate of major adverse cardiovascular events was not significantly lower with bivalirudin than with heparin (10.3% and 10.9%, respectively; relative risk, 0.94; 95% confidence interval [CI], 0.81 to 1.09; P=0.44), nor was the rate of net adverse clinical events (11.2% and 12.4%, respectively; relative risk, 0.89; 95% CI, 0.78 to 1.03; P=0.12). Post-PCI bivalirudin infusion, as compared with no infusion, did not significantly decrease the rate of urgent target-vessel revascularization, definite stent thrombosis, or net adverse clinical events (11.0% and 11.9%, respectively; relative risk, 0.91; 95% CI, 0.74 to 1.11; P=0.34). CONCLUSIONS In patients with an acute coronary syndrome, the rates of major adverse cardiovascular events and net adverse clinical events were not significantly lower with bivalirudin than with unfractionated heparin. The rate of the composite of urgent target-vessel revascularization, definite stent thrombosis, or net adverse clinical events was not significantly lower with a post-PCI bivalirudin infusion than with no post-PCI infusion. (Funded by the Medicines Company and Terumo Medical; MATRIX ClinicalTrials.gov number, NCT01433627.).

Hepcidin in obese children as a potential mediator of the association between obesity and iron deficiency.

CONTEXT Obesity and iron deficiency are two of the most common nutritional disorders worldwide. Several studies found higher rates of iron deficiency in obese than in normal-weight children. Hepcidin represents the main inhibitor of intestinal iron absorption, and its expression is increased in adipose tissue of obese patients. Leptin is able, in vitro, to raise hepcidin expression. OBJECTIVES Aims of this work were 1) to assess the association between poor iron status and obesity, 2) to investigate whether iron homeostasis of obese children may be modulated by serum hepcidin variations, and 3) to assess the potential correlation between leptin and serum hepcidin variations. METHODS Iron status and absorption as well as hepcidin, leptin, and IL-6 levels were studied in 60 obese children and in 50 controls. RESULTS Obese children showed lower iron and transferrin saturation (both P < 0.05) and higher hepcidin levels (P = 0.004) compared with controls. A direct correlation between hepcidin and obesity degree (P = 0.0015), and inverse correlations between hepcidin and iron (P = 0.04), hepcidin and transferrin saturation (P = 0.005), and hepcidin and iron absorption (P = 0.003) were observed. A correlation between leptin and hepcidin (P = 0.006) has been found. The correlation remained significant when adjusted for body mass index, sex, pubertal stage, and IL-6 values. CONCLUSIONS We propose that in obese patients, increased hepcidin production, at least partly leptin mediated, represents the missing link between obesity and disrupted iron metabolism.

Visceral adiposity and arterial stiffness: echocardiographic epicardial fat thickness reflects, better than waist circumference, carotid arterial stiffness in a large population of hypertensives

AIMS Relationship between obesity and cardiovascular (CV) disease depends not only on the amount of body fat, but also on its distribution. For example, individuals with increased fat accumulation in the abdominal region have atherogenic lipid profiles and are at increased CV risk. The loss of elasticity in medium and large arteries is an early manifestation of atherosclerosis. The aim of this study was to evaluate whether echocardiographic epicardial adipose tissue, an index of cardiac adiposity, is related to carotid stiffness and carotid intima-media thickness (IMT), indexes of subclinical atherosclerosis, better than waist circumference in hypertensive patients. METHODS AND RESULTS We studied 459 patients with Grade I and II essential hypertension who were referred to our outpatient clinic over a period from May 2007 to March 2008. The population was first sorted by waist circumference and then by epicardial fat < or = 7 or >7 mm. We measured epicardial fat thickness, waist circumference, carotid artery stiffness, and carotid IMT in all patients. Patients divided according to waist circumference showed no statistical differences in carotid artery stiffness between the two groups. Subjects with epicardial fat >7 mm were older, had higher systolic, diastolic, and pulse pressure, increased left ventricular mass index, carotid IMT, diastolic parameters, and stiffness parameters compared with those with epicardial fat < or = 7 mm (P < 0.001). A positive correlation was found between epicardial fat and age, pulse pressure, stiffness parameters, carotid IMT, systolic blood pressure, and duration of hypertension, and a negative correlation was found with diastolic parameters. Age, carotid IMT, and stiffness parameters were independently related to epicardial fat. CONCLUSION Our findings indicate that epicardial fat reflects carotid artery stiffness in hypertension-induced organ damage.

CRP and the risk of atherosclerotic events

A large body of literature supports the idea that inflammation plays a pivotal role in all phases of atherosclerosis, from the fatty streak lesion formation to the acute coronary event due to vulnerable plaque rupture. Indeed, vascular inflammation contributes to the pathogenesis of atherosclerosis, and later in the disease process, it is a major determinant for the acute coronary syndromes. There are various inflammatory markers that have been shown to predict cardiovascular events. These include high-sensitivity C-reactive protein (hs-CRP), a simple downstream marker of inflammation, recently emerged as a major cardiovascular risk factor. Elevated baseline concentrations of hs-CRP are associated with the risk of atherosclerotic events in general populations and show a predictive value even in terms of secondary prevention, both in patients with chronic stable angina and acute coronary syndromes. In recent year, a lot of concerns have emerged about the experimental models used to study the role of CRP in atherosclerosis; moreover, the results of trials evaluating the clinical association between this molecules and outcome are still controversial. In this paper, we attempt to review the pathophysiological evidences about the link between CRP and atherosclerosis and, most notably, about its utility as a marker and risk predictor in various clinical settings. The identification of specific triggers and mechanisms of underlying inflammation and a better understanding of each step involved in this complex process might lead to new ways to manage patients with atherosclerosis, both in terms of primary and secondary prevention, and CRP still appears to be a suitable candidate for this purpose.

Inflammation and Cardiovascular Disease: From Pathogenesis to Therapeutic Target

Atherosclerosis represents the most common pathological substrate of coronary heart disease (CHD), and the characterization of the disease as a chronic low-grade inflammatory condition is now largely accepted. A number of mediators of inflammation have been widely studied, both as surrogate biomarkers and as causal agents, in the pathophysiological network of atherogenesis and plaque vulnerability. The epidemiological observation that biomarkers of inflammation are associated with clinical cardiovascular risk supports the theory that targeted anti-inflammatory treatment appears to be a promising strategy in reducing residual cardiovascular risk on the background of traditional medical therapy. A large number of randomized controlled trials have shown that drugs commonly used in cardiovascular disease (CVD), such as statins, may be effective in the primary and secondary prevention of cardiovascular events through an anti-inflammatory effect. Moreover, several anti-inflammatory drugs are being tested for their potential to reduce residual cardiovascular risk on the background of validated medical therapy for atherosclerotic disease. In this paper, we review relevant evidence with regard to the relationship between inflammation and CVD, from pathogenesis to therapeutic strategies.

Effect of body mass index reduction on serum hepcidin levels and iron status in obese children.

Iron deficiency has been linked to obesity. Hepcidin is the main regulator of iron homeostasis and is higher in obese children compared to controls. To gain insight into the link between obesity and hepcidin, we performed an intervention study in 15 obese children. These children were subjected to a 6-month weight loss program and underwent physical examination and iron status and absorption as well as hepcidin, interleukin-6 and leptin serum levels evaluation at baseline and after the weight loss program. After the program all children reduced their body mass index standard deviation score (BMI SDS) of at least 0.5. We observed a significant decrease in hepcidin (P=0.003) and leptin levels (P=0.005), and a significant increase in iron absorption (P=0.02). A direct correlation between the measure of hepcidin and leptin reduction was observed and this correlation appeared significant (r2=0.33, P=0.003) when adjusted for interleukin-6 and BMI SDS variations. In conclusion, we have shown that, in obese children, BMI reduction is associated with hepcidin reduction, potentially improving iron status and absorption. Implications of these findings could be considered in the management of obese children with poor iron status.

Association between left atrial myocardial function and exercise capacity in patients with either idiopathic or ischemic dilated cardiomyopathy: A two-dimensional speckle strain study

BACKGROUND In patients with idiopathic dilated cardiomyopathy (DCM) a more depressed left atrial (LA) booster pump function has been observed compared to ischemic patients although under similar loading conditions, and attributed both to altered LA overload and to LA larger involvement in the myopathic process. AIM OF THE STUDY To detect by speckle-tracking two-dimensional strain (2DSE) LA systolic dysfunction in patients with either idiopathic or ischemic DCM, and to assess in these patients possible correlation between LA myocardial function and exercise capacity during cardiopulmonary test. METHODS Three-hundred-fourteen patients (52.4+/-11.2 years) with either idiopathic (160 patients) or ischemic (154 patients) DCM underwent cardiopulmonary stress test, standard Doppler echo and 2DSE analysis of atrial longitudinal strain in the basal segments of LA septum and LA lateral wall, and in LA roof. RESULTS The two groups were comparable for most of clinical variables. LV volumes, ejection fraction, stroke volume, and mitral valve effective regurgitant orifice were similar between the two groups. No significant differences were evidenced in Doppler transmitral inflow measurements. Also LA diameter and maximal volume were similar between the two groups. Conversely, LA active empting volume and fraction were both lower in patients with idiopathic DCM (<0.001). Peak systolic myocardial atrial strain was significantly reduced in patients with idiopathic DCM compared with ischemic DCM at the level of all the analyzed atrial segments (p<0.0001). By multivariable analysis, in the overall population, ischemic aetiology of DCM (p<0.0001) and LA volume (p<0.001) were the only independent determinants of LA lateral wall systolic strain. On the other hand, LA lateral wall systolic strain (p<0.0001) and LA volume (p<0.001) were powerful independent predictors of peak oxygen consumption during cardiopulmonary exercise testing. CONCLUSIONS Two-dimensional strain represents a promising non-invasive technique to assess LA atrial myocardial function in patients with DCM. LA systolic deformation is more depressed in idiopathic compared with ischemic DCM, and is closely associated with functional capacity during effort. Future longitudinal studies are warranted to further our understanding of the natural history of LA myocardial function, the extent of reversibility of LA dysfunction with therapy, and the possible prognostic impact of such indexes in patients with congestive heart failure.

Adipose tissue-mediated inflammation: the missing link between obesity and cardiovascular disease?

Until relatively recently, the role of adipose tissue in the development of obesity and its consequences was considered to be a passive one. Mounting evidence highlights the role of adipose tissue in the development of a systemic inflammatory state that contributes to obesity-associated vasculopathy and cardiovascular risk. It is now clear that, in addition to storing calories as triglycerides, adipocytes secrete a large variety of cytokines, chemokines and hormone-like factors, such as leptin, resistin, and acute-phase proteins. In addition, insulin resistance, both in nondiabetic and diabetic subjects, is frequently associated with obesity, particularly with an excess of intraabdominal fat. This production of pro-atherogenic substances is of particular interest since an increase in the plasma levels of these mediators may provide a novel mechanistic link between obesity and its vascular complications.