Search

To evaluate right ventricular function in patients with beta-thalassaemia major and congestive heart failure. Background In patients with beta-thalassaemia major a high incidence of cardiac involvement still exists despite improved prognosis with chelation therapy. Development of severe right heart failure is common and has been attributed to pulmonary hypertension secondary to lung haemochromatosis. However, the possibility of direct right ventricular myocardial involvement in the absence of significant pulmonary hypertension has not been adequately investigated.Twenty-nine consecutively screened patients with beta-thalassaemia major and congestive heart failure were investigated by Doppler echocardiography, right ventricular first-pass radionuclide examination and cardiac catheterization. Haemodynamic data were obtained both before and after volume loading. A control group of 39 patients with beta-thalassaemia major, free from cardiac disease, and matched for age, gender, body surface area and heart rate was used for comparison. A subset of the control thalassaemic group (n=15) underwent both radionuclide and haemodynamic assessment.The majority of patients were on non-optimal chelation therapy. Only two of 29 patients were found to have cor pulmonale. One other patient suffered from constrictive pericarditis. A restrictive filling pattern in both ventricles and left ventricular systolic dysfunction were evident in the other 26 patients. Pulmonary artery pressure (systolic, 33+/-8 vs 27+/-5 mmHg, P0.05) and pulmonary vascular resistance (114+/-56 vs 65+/-29 dynes. s. cm(-5), P0.01) were only mildly elevated in the heart failure group. After volume challenge, cardiac output remained unchanged although the increments of ventricular filling pressures were significant (Deltaright atrial: 4.8+/-2.2 mmHg, P0.05; Deltapulmonary capillary wedge: 5.6+/-2.9 mmHg, P0.05) and correlated with each other (r=0.69;P0.001) in heart failure patients, suggesting pericardial constraint and ventricular interaction. In these patients compared with the control thalassaemic group, a lower right ventricular ejection fraction (29%+/-9 vs 59%+/-6, P0.0001) without correlation with pulmonary artery pressures was found. Haemodynamically significant right ventricular dysfunction defined as mean right atrial pressure10 mmHg and ratio of mean right atrial-to-capillary wedge pressure0.8 was evident in 15 of the 26 patients (58%), all with severe symptoms, representing three fourths of the patients in functional class III and IV. Simultaneous pressure recordings in six of these 15 patients showed equalization of ventricular end-diastolic pressures within 5 mmHg.The majority of patients with beta-thalassaemia major and severe congestive heart failure demonstrated a unique haemodynamic pattern similar to that described in predominant right ventricular infarction, indicating severe right ventricular cardiomyopathy in addition to left ventricular dysfunction. The incidence of cor pulmonale as a cause of right heart failure seems to be much lower than previously hypothesized.

Inflammation is a key feature of atherosclerosis and its clinical manifestations. The leukocyte count has emerged as a marker of inflammation that is widely available in clinical practice. Since inflammation plays a key role in atherosclerosis and its end results, discovering new biomarkers of inflammation becomes important in order to help diagnostic accuracy and provide prognostic information about coronary cardiac disease. In acute coronary syndromes and percutaneous coronary intervention, elevated levels of almost all subtypes of white blood cell counts, including eosinophils, monocytes, neutrophils, and lymphocytes, and neutrophil–lymphocyte ratio and eosinophil–leukocyte ratio constitute independent predictors of adverse outcomes. Eosinophil count and eosinophil–leukocyte ratio, in particular, emerge as novel biomarkers for risk stratification in patients with coronary artery disease. Since the presence of eosinophils denotes hypersensitivity inflammation and hypersensitivity associated with Kounis syndrome, this reality is essential for elucidating the etiology of inflammation in order to consider predictive and preventive measures and to apply the appropriate therapeutic methods.

Objective Radial artery spasm may hinder completion of transradial angiography or PCI, leading to access site crossover, prolonged procedure times and complications. The aim of this study was to derive a radial artery spasm risk score in patients undergoing elective percutaneous coronary intervention (PCI), prospectively validate it, and apply it in a real-life clinical setting. Methods The study population consisted of 3 cohorts of patients undergoing elective PCI with transradial access: the derivation cohort (N=1006), the validation cohort (N=576) and the intervention cohort (N=140), consisting of patients with high risk score, in whom intensified spasm-preventive measures were applied. Results Multivariable analysis in the derivation cohort showed that 5 weighted factors could be used to construct a risk score for spasm: body-mass index, height, current smoking, hypertension and peripheral artery disease (c-statistic 0.945, with an optimal cut-off of 4). In the validation cohort, the cut-off of 4 predicted spasm with a sensitivity of 84.5% and a specificity of 74.7%. In the intervention cohort, which included only patients with a spasm-risk score of ≥4, the rate of spasm was drastically reduced (odds ratio 0.32, 95% confidence interval 0.17–0.61), compared to the corresponding high spasm risk subgroup of patients of the validation cohort. Conclusion A spasm risk score can be used to predict radial artery spasm during elective transradial PCI. Using this score, a high spasm risk patient subgroup can be identified, where intensive spasm-preventive measures can lead to a significant reduction in the frequency of spasm.

Metallic devices are increasingly used in contemporary cardiological practice. They include coronary stents, artificial cardiac valves, bioprostheses for transcatheter aortic valve replacement, closure devices for patent foramen ovale and atrial septal defects, pacemakers, defibrillators, and left ventricular assist devices. Metals constitute the main components of these devices. Metal anions eluted from the components attached to circulating proteins can act as sensitizers able to induce hypersensitivity inflammation and thrombosis. Allergy to nickel occurs in up to one fourth of the population in several areas of the world and is the most frequent cause of allergic contact dermatitis. The HeartMate II device is made from titanium with ruby bearing. Titanium metal ions from HeartMate II are eluted through the action of blood, saline, proteins, and mechanical stress that can induce hypersensitivity and immune dysfunctions rendering titanium no longer biologically inert. An unexpected high rate of thrombosis with substantial morbidity and mortality has been observed with the use of this device, making the search of causality of thrombosis mandatory to predict and prevent this daunting complication. Although the cause of thrombosis seems to be multifactorial, careful history-taking regarding hypersensitivities, monitoring of inflammatory mediators, and lymphocyte transformation studies should be always performed in sensitive patients.

We sought to test the hypothesis that virtual histology characteristics of the culprit lesion in patients with ST-elevation myocardial infarction are associated with blood flow restoration after thrombolysis.Consecutive patients referred for coronary angiography after successful thrombolysis were included in this correlational cross-sectional study. Evaluation with intravascular ultrasound (IVUS) and virtual histology of the culprit arterial segment was performed in all cases.Forty-eight patients (60.5 ± 10.7 years) were included. TIMI flow grade 3 was found in 24 (50%). Diabetes was strongly associated with lower TIMI flow 3 rate (26.7% vs 60.6%; p = 0.029) and there was a significant difference in the time to thrombolysis (2.0 ± 0.8 hours in those with TIMI flow 3 vs 3.0 ± 0.7 hours in TIMI flow grades 1-2; p0.001). Patients with TIMI flow grades 3 and 1-2 had similar absolute total plaque volume (152.8 ± 59.3mm(3) vs 147.5 ± 92.3mm(3); p = 0.817) and absolute necrotic core (NC) volume (31.2 ± 13.9 mm(3) vs 33.6 ± 23.2mm(3); p = 0.671). However, there were significant differences in the relative NC content, both in proportion to the whole plaque volume (26.3% vs 29.9%; p = 0.016) and as an area fraction at the largest NC site (31.5% vs 40.3%; p0.001).The NC content of atherosclerotic plaques is meaningful for flow restoration after the occurrence of a coronary event. This finding highlights the importance of plaque composition, as studied with virtual histology, not only for the sequence of processes leading to an acute plaque-related event, but also for thrombus formation and lysis, following the occurrence of such an event.

The relation of coronary artery calcification with the presence of symptoms of coronary artery disease and its angiographic severity is not clear. We studied 37 apparently healthy, asymptomatic subjects that were found by digital cinefluoroscopy to have coronary calcium and compared to age- and sex-matched group of patients with coronary calcium and symptomatic coronary artery disease. Normal coronary arteries and non-obstructive lesions only were found in 12/37 (32.4%) and 11/37 (29.7%) asymptomatic subjects vs. 1/37 (2.7%) and 2/37 (5.4%) patients; P

Background Cardiac hemochromatosis remains the most frequent cause of death in β-thalassemia major. Previous studies suggest an important right ventricular (RV) contribution to cardiac morbidity and mortality. Studies with Doppler echocardiography have shown contradictory results regarding left ventricular (LV) filling, whereas the RV filling characteristics have not been studied yet. We prospectively studied the pattern of RV filling and investigated echocardiographic and clinical correlates during baseline and follow-up examinations in patients with β-thalassemia major. Methods and Results The study included 79 patients, aged 24.2 ± 8.0 years, with homozygous β-thalassemia major without symptoms of heart failure with normal LV function and 51 healthy control subjects, matched for age, sex, and body surface area. Doppler echocardiographic indexes of systolic and diastolic ventricular function were assessed. Hemodynamic measurements were obtained in 8 patients by right heart catheterization. An abnormal RV relaxation pattern was evident in the patient group. The LV filling characteristics indicated increased preload without abnormal alteration, whereas catheterization findings were consistent with a high cardiac output state. Short tricuspid deceleration time (DT) had the best predictive value for subsequent cardiac events. Repeat echocardiographic study in 35 asymptomatic patients at 19 ± 7 months demonstrated deterioration of LV systolic function, chamber enlargement, and shortening of DT of tricuspid and mitral inflow. Conclusions In patients with homozygous β-thalassemia major without cardiac disease, the pattern of RV filling is abnormally altered, indicating impaired relaxation. In contrast, the LV filling is compatible with increased preload, as in chronic anemia. Short DT of early tricuspid inflow carries important prognostic value. LV remodeling occurs over time along with transition toward a restrictive ventricular filling pattern. (Am Heart J 2001;141:428-34.)

The pathophysiology of vasculopathy of cardiac allografts is still unknown. Coronary vasospasm and thrombosis are some rare manifestations accompanying this entity. Hypersensitivity processes and the hypersensitivity coronary syndrome (Kounis syndrome) may be associated with this potentially fatal complication. Research efforts towards this direction may shed light for prevention and treatment of this disease.

Proton pump inhibitors are commonly used in clinical practice for the treatment of peptic ulcer and gastroesophageal reflux and are well tolerated by the patients. Their use is rarely associated with hypersensitivity and anaphylactic reactions. According to the reports in the Uppsala Monitoring Center database the frequency of hypersensitivity reactions out of all reported adverse reactions for proton pump inhibitors and H2-histamine receptor antagonists was between 0.2% and 0.7%. A few cases of hypersensitivity to lansoprazole have been reported. We report a patient who developed Kounis syndrome after taking 30 mg of lansoprazole. This is the first report of Kounis syndrome associated with lansoprazole administration in the world literature.

A 58-year-old man with no history of cardiac diseases or cardiovascular risk factors was stung by honeybees. Soon after, he gradually developed signs of an allergic reaction followed by severe retrosternal pain. Electrocardiographic, echocardiographic evidence and positive biochemical markers were consistent with an acute anterolateral myocardial infarction. Coronary arteriography showed a left anterior descending artery thrombotic lesion. This is a case of Kounis syndrome, which is the concurrence of acute coronary syndromes with conditions associated with mast cell activation including allergic or hypersensitivity reactions as well as anaphylactic or anaphylactoid insults. The clinical implications and pathophysiology of this dangerous association are discussed.

Sir, Takotsubo syndrome, transient left ventricular apical ballooning, takotsubo cardiomyopathy, apical ballooning syndrome, atypical apical ballooning, ampulla cardiomyopathy, broken heart syndrome, transient left ventricular dysfunction syndrome, and stress cardiomyopathy were named after a round-bottomed and narrow-necked fishing pot - takotsubo in Japanese - for trapping octopus because of its resemblance to left ventriculogram. In the interesting report published in Indian Journal of Critical Care Medicine,[1] a 48-year-old man with progressive loss of vision, hypotension, tachycardia, and acidosis was found to have takotsubo syndrome while the coronary arteries were normal. Computerized tomography revealed dense sellar-suprasellar mass lesion extending into the hypothalamus resembling pituitary adenoma with hypocortisolism suggesting hypopituitarism. With dobutamine, atenolol, and noradrenaline, his condition improved. This case raises some issues concerning neurological conditions, mental stress adrenaline, anaphylaxis, and Kounis syndrome. Mental stress commences with impulses from high brain cortical centers that are relayed through the limbic system to hypothalamus resulting in the release of corticotropin-releasing hormone (main coordinator of the mental stress response) and norepinephrine, serotonin, acetylcholine, proopiomelanocortin, adrenocorticotropic hormone, glucagon, growth hormone, and homocysteine that stimulate sympathetic nervous system. These substances can induce heightened cardiovascular activity, endothelial injury, induction of adhesion molecules on the endothelial cells, to which recruited inflammatory cells adhere and translocate to the arterial wall and finally myocardial damage. An acute phase response is engendered, resulting in production of cytokines interleukin-1 (IL-1), IL-6, tumor necrosis factor-alpha, acute phase proteins, macrophage, mast cell, and platelet activation that eventually culminate in the development of Kounis syndrome.[2] Stress-induced cytokine production has been incriminated for multivessel coronary artery spasm at epicardial or microvascular levels that induce takotsubo cardiomyopathy. Inflammatory mediators released during anaphylaxis can induce coronary spasm and takotsubo syndrome and adrenaline given for anaphylaxis might contribute to coronary spasm and transient takotsubo syndrome. Adrenaline and noradrenaline released by the renin-angiotensin-aldosterone system together with histamine stimulate the release of more catecholamines by direct action on the adrenal medullary cells. Administration of catecholamines for hemodynamic support of anaphylactic shock would also increase the plasma catecholamines. Catecholamine increase in patients with angina, renders blood platelets more sensitive and more prone to aggregation and thrombosis. Therefore, measurement of anaphylactic inflammatory mediators including histamine, chymase, leukotrienes, thromboxane, and platelet activating factor or the use of corticosteroids or mast cell stabilizers for prevention and treatment may shed light on etiology and pathophysiology of takotsubo cardiomyopathy. The concurrence of acute coronary syndromes with conditions associated with mast cell activation, involving interrelated and interacting inflammatory cells constitute the Kounis syndrome.[3] Inflammatory cells, such as mast cells, T-cells, and macrophages, activate each other via multidirectional stimuli and release mediators capable to induce coronary events. Experimental findings suggest that cardiac mast cell activation by acute stress may contribute to myocardial ischemia through the release of histamine or proinflammatory mediators.[4] Therefore, takotsubo cardiomyopathy should be always considered in neurological conditions with prolonged addisonian crisis. Furthermore, Adrenaline, takotsubo, Anaphylaxis, and Kounis syndrome (ATAK) seem to constitute a challenging contemporary complex that needs inexorable “attack” to elucidate its etiology, pathophysiology, and treatment.[5] Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest

Background We aimed to examine the diagnostic value of ST-segment depression in patients with rapid atrial fibrillation (AF) for the prediction of coronary artery disease (CAD). Methods Hemodynamically stable patients with AF, and a heart rate > 80% of their maximum predicted according to their age, were allocated to 2 groups according to their electrocardiographic findings on admission: group A included patients without any ST-segment abnormalities and group B, patients with downward or horizontal ST-segment depression ≥ 1 mm in 2 or more contiguous leads. Group A patients were subjected to a dobutamine stress echo or Tl-201 myocardial single-photon emission computed tomography, followed by coronary angiography in case of abnormal results and Group B patients to coronary angiography. CAD was defined angiographically as stenosis of ≥ 50% in any major epicardial coronary vessel. Results Out of 115 consecutive patients, with a mean age of 65.9 ± 10.2 years, 42.6% were male, 18.3% smokers, 68.7% hypertensive, 21.7% had diabetes, and 40% had hyperlipidemia. We enrolled 71 and 44 patients in group A and B, respectively. Prevalence of significant CAD among studied patients was 21.7%, 3/71 (4.2%) and 22/44 (50.0%) in group A and B, respectively. Overall ST-segment depression during rapid AF had 88.0% sensitivity (95% confidence interval [CI], 67.7%-96.8%) and 75.6% specificity (95% CI, 65.2%-83.7%) in predicting presence of CAD, and positive and negative predictive value was 50.0% (95% CI, 34.8%-65.2%) and 95.8% (95% CI, 87.3%-98.7%), respectively. Conclusions In consecutive patients with rapid AF, the absence of ST-segment depression might indicate absence of CAD.

Monoclonal antibodies are currently used in the treatment of neoplastic, hematological, or inflammatory diseases, a practice that is occasionally associated with a variety of systemic and cutaneous adverse events. Cardiac adverse events include cardiomyopathy, ventricular dysfunction, arrhythmias, arrests, and acute coronary syndromes, such as acute myocardial infarction and vasospastic angina pectoris. These events generally follow hypersensitivity reactions including cutaneous erythema, pruritus chills, and precordial pain. Recently, IgE specific for therapeutic monoclonal antibodies have been detected, pointing to the existence of hypersensitivity and Kounis hypersensitivity-associated syndrome. Therefore, the careful monitoring of cardiovascular events is of paramount importance in the course of monoclonal antibody-based therapies. Moreover, further studies are needed to elucidate the pathophysiology of cardiovascular adverse events elicited by monoclonal antibodies and to identify preventive, protective, and therapeutic measures.

Evidence suggests that inflammation, both local and systemic, plays an important role in the pathogenesis of acute myocardial infarction [1]. There is also evidence that increased concentrations of inflammatory markers such as C-reactive protein interleukin-2 and tumor necrosis factor can identify patients at high risk of future ischemic events, suggesting that the intensity of the inflammatory response influences clinical outcome in acute coronary syndromes [2, 3]. Multiple studies have demonstrated also an association between elevated leucocyte count, which is a non-specific marker of inflammation, and the extent of coronary artery disease or increased short-term or long-term risk of death in patients with various manifestations of coronary artery disease [4, 5]. Other studies [6] have shown that total leucocyte count, but not C-reactive protein, predicts 1-year mortality in patients with acute coronary syndromes treated with percutaneous coronary intervention. Furthermore, recent studies have emphasized the usefulness of neutrophil to lymphocyte ratio in predicting short-and long-term mortality, thrombus formation, infarct related artery patency, TIMI flow grade after primary coronary angioplasty, impaired myocardial perfusion, ventricular arrhythmias and critical limb ischemia [7–9]. Indeed, in patients with non-ST-elevation myocardial infarction a ratio above 4.7 has been reported to be an independent predictor of short-term and long-term mortality [7] and ratio[3.3 was found to be an independent predictor of impaired coronary flow after primary percutaneous coronary intervention and of in-hospital major adverse cardiac events in patients with ST-segment elevation myocardial infarction [10]. In a recent issue of the Int J Cardiovasc Imaging [11] and additional very interesting paper was published which shows that in patients undergoing primary percutaneous coronary intervention for ST-segment elevation myocardial infarction an elevated baseline white blood count is associated with less salvaged myocardium, larger infarct size and poorer clinical outcomes. All these papers and results really suggest a key role of inflammation in coronary artery disease. However, differential count was not available in these studies, and therefore, assessing the relative impact of white blood count subpopulations on myocardial infarction was not reported. Total white blood count comprises several cell types such as monocytes, lymphocytes and eosinophils all of which are implicated in the development, progression and instability of atherosclerotic plaque. None of the above studies have focused attention on the presence of eosinophils and this was probably based on an older study which has suggested that total white blood count is a better correlate of long-term than differentials [12]. Eosinophils, however, play an important role in inflammation and can identify the etiology of inflammation since they denote hypersensitivity inflammation [13–15]. Eosinophils are pleiotropic multifunctional leukocytes involved in initiation and propagation of inflammatory responses and thus have important roles in the pathogenesis of inflammatory diseases. These cells are also bone marrow-derived granulocytic leukocytes which express H4 histamine receptors in their surface. These receptors facilitate eosinophil chemotaxis toward mast cells which are the major producers of an array of inflammatory soluble mediators. These inflammatory mediators can induce the coronary hypersensitivity associated Kounis syndrome manifesting as vasospastic angina and/or acute myocardial N. G. Kounis (&) Medical Sciences, Patras Highest Institute of Education and Technology, Patras, Achaia, Greece e-mail: ngkounis@otenet.gr

The prevalence of contraindications/special warnings and precautions (CON/SWP) for clopidogrel, prasugrel and ticagrelor use is not adequately studied and might affect P2Y12 inhibitor choice in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI).In the context of the GReek AntiPlatelet rEgistry (GRAPE) a detailed recording of CON/SWP for use of clopidogrel, prasugrel and ticagrelor was done for 1,280 consecutive, moderate-high-risk ACS patients undergoing PCI. At least 1 CON for use of clopidogrel, prasugrel and ticagrelor was present in 5 (0.4%), 49 (3.8%) and 12 patients (0.9%), respectively. Prevalence of at least 1 CON/SWP to clopidogrel (45.8%) was less frequent compared to prasugrel (49.1%) or ticagrelor (49.1%; P=0.02 and P=0.04, respectively), while 34% of patients had at least 1 CON/SWP to all the 3 P2Y12 inhibitors. At discharge, 482 (38.6%), 301 (24.1%) and 464 patients (37.2%) received clopidogrel, prasugrel and ticagrelor, respectively. Age ≥75 years, co-medication related to increased bleeding risk, and history of asthma/chronic obstructive pulmonary disease favored clopidogrel vs. prasugrel or ticagrelor use as discharge medication, while geographic region also affected this choice (C-statistic, 0.81; 95% CI: 0.78-0.83).In patients with ACS undergoing PCI the prevalence of CON to antiplatelet agents is low, whereas that of SWP is high. Certain SWP, along with regional trends may affect the choice of newer P2Y12 inhibitors vs. clopidogrel.

Radial artery occlusion (RAO) remains the "Achilles heel" of transradial coronary procedures. Higher over lower levels of systemic anticoagulation are believed to reduce RAO rates but this is ill-supported by scientific evidence. This was a prospective, randomized, single-center study of parallel

In a very interesting study published in Forensic Science,Medicine, and Pathology [1] it was found that measure-ment of eosinophils and mast cells in the spleen combinedwith serum tryptase measurement could diagnose anaphy-laxis and anaphylactic death with a high degree of cer-tainty. The authors stated that anaphylactic death cannot bediagnosed by autopsy alone or by counting mast cells in thelung and airways because these methods have failed to giveconsistent results. The search for other tissues infiltrated byallergic inflammatory cells could prove of paramountimportance in diagnosing anaphylactic sudden death. Theyrecommended that splenic tissue should be sampled forimmunohistochemical examination in all cases of unwit-nessed sudden death.Eosinophils, mast cells, and basophils are importanteffector cells in the allergic response and they have beenimplicated in the pathogenesis of anaphylaxis. Whilediagnosing the cause of sudden death is a challenging taskfor both physicians and forensic pathologists, anaphylacticetiology is rarely suspected. Frequently, sudden death casesare attributed to myocardial involvement, but unrecognizedanaphylaxis may accompany up to 13 % of sudden unex-pected deaths in adults [2]. There is experimental andclinical evidence that anaphylaxis is frequently associatedwith myocardial involvement due to coronary artery spasmand thrombosis manifesting as Kounis type I and Kounistype II variant [3]. Some experiments have shown thatanaphylactic cardiac damage is not due to peripheralvasodilation but is the result of the action of anaphylacticmediators on the coronary vasculature [4]. Clinically, thereare patients with anaphylactic cardiac shock who do notrespond to fluid replacement but need anti-allergic andcurrent myocardial infarction protocol treatment, thusdenoting that the heart and especially the coronary arteriesare primarily affected [5, 6]. However, differentiatingglobal myocardial hypoperfusion from a primary cardiacmyocardial suppression due to mast cell mediator action isclearly challenging and combined myocardial suppressionand peripheral vasodilatation might occur simultaneously.There are reports of sudden death due to coronary arteryspasm in which the coronary arteries are involved. In apatient with repeated episodes of coronary spasm, who diedsuddenly following cessation of his treatment, the numberof adventitial mast cells was found to be increased [7]. Inthis patient, histologic sections in all three major coronaryarteries, including the area of spasm, were stained withtoluidine blue and showed increased mast cells. In the samereport, two additional subjects with sudden cardiac deathalso had increased mast cells in their coronary arteries withthe highest counts in atherosclerotic and hemorrhagic pla-ques. Furthermore, coronary arteries of cardiac patients arehyper-reactive and contain stores of amines deriving frominflammatory cells that are the main culprits in inducingcoronary spasm [8]. Type I and type II variants of theKounis syndrome have led to coronary artery spasm andsudden death in two patients with drug-eluting stents. It is

Background— The ulnar artery is rarely selected for coronary angiography or percutaneous coronary intervention despite the expanding use of the transradial approach. We aimed to establish noninferiority of a default transulnar relative to transradial approach in terms of feasibility and safety. Methods and Results— This was a prospective, randomized, multicenter, parallel-group study involving 902 patients at 5 sites eligible to undergo diagnostic coronary angiography and percutaneous coronary intervention. Patients were randomized in a 1:1 ratio to either transradial approach (reference intervention) or transulnar approach (experimental intervention) regardless of the Allen test results. The primary end point was a composite of cross-over to another arterial access, major adverse cardiovascular events, and major vascular events of the arm at 60 days. The study was prematurely terminated after the first interim analysis because of inferiority of the transulnar approach. Although the difference in the primary end point became inconclusive after adjustment for operator clustering (24.30%; 99.99% confidence interval [CI], −7.98% to 56.58%; P =0.03 at α=0.0001), need for cross-over in the transulnar group remained inferior to transradial access site with a difference of 26.34% (95% CI, 11.96%–40.69%; P =0.004). Conclusions— As a result of higher cross-over rates, a first-line transulnar strategy was proven inferior to the transradial approach for coronary procedures. At present, the transulnar route should not be regarded as an acceptable alternative to the transradial access site. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01364532.

Background— Prasugrel and ticagrelor provide a superior anti-ischemic action than clopidogrel, with some of ticagrelor’s benefits possibly attributed to adenosine-mediated mechanisms. We aimed to compare the effect of maintenance dose of ticagrelor versus prasugrel on coronary blood flow velocity (CBFV) during increasing doses of intravenously administered adenosine. Methods and Results— In a prospective, single-center, single-blind, crossover study, 56 patients with non–ST-elevation acute coronary syndrome undergoing percutaneous coronary intervention were randomized to receive either ticagrelor 90 mg BID or prasugrel 10 mg OD with a 15-day treatment period. At the end of each treatment period, CBFV by transthoracic Doppler echocardiography was assessed at baseline and under incremental doses (50 μg/kg per minute, 80 μg/kg per minute, 110 μg/kg per minute, and 140 μg/kg per minute) of adenosine infusion. Maximal CBFV area under the curve was higher for ticagrelor-treated than for prasugrel-treated patients, with a least squares mean difference of 7.16 (95% confidence interval, 2.61–11.7; P =0.003). Maximal CBFV/baseline CBFV ratio was higher with ticagrelor than prasugrel at 50, 80, and 110 μg/kg per minute but not at 140 μg/kg per minute adenosine infusion rate, with mean difference (95% confidence interval) of 0.17 (0.08–0.26; P P =0.03), 0.24 (0.01–0.47; P =0.04), and 0.14 (−0.12 to 0.4; P =0.3), respectively. Conclusions— In patients with non–ST-elevation acute coronary syndrome undergoing percutaneous coronary intervention, ticagrelor augments CBFV to a greater extent than prasugrel when incremental doses of adenosine are administered. Although exploratory, these results may represent a pleiotropic action of ticagrelor, possibly contributing to its beneficial effects in such patients. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01642966

We would like to thank Drs Grove and Kristensen for their interest in our recently published article on ticagrelor versus prasugrel antiplatelet action in the acute phase of ST elevation myocardial infarction.1 The authors have proposed that an increased platelet turnover in ST elevation myocardial infarction may reduce the effect of antiplatelet drugs. Their suggestion is on the basis of previous observations involving 16 patients, …

Identification of factors affecting platelet reactivity (PR) and high PR (HPR) or high platelet inhibition (HPI) rates while on prasugrel maintenance dose (MD) might be helpful in avoiding ischemic or bleeding complications. We retrospectively analyzed all patients (n=233) treated in our institution between April 2010 and November 2012 who had platelet function assessment pre-prasugrel and following prasugrel 10 mg MD for at least 5 days, using the Verify Now P2Y12 platelet function assay. Multiple linear regression and logistic regression models were applied to identify independent factors affecting post-prasugrel PR level, HPR and HPI status. The amount of variance in PR under prasugrel MD that could be explained by the model was 25.9% (adjusted R²), p0.001. Pre-prasugrel treatment PR, acute coronary syndrome (ACS), prasugrel loading and smoking uniquely accounted for 10.8%, 1.3%, 3.5% and 1.2% of the observed variance, respectively. HPR and HPI were observed in 7.7% and 13.7% of the cases, respectively. On multivariate analysis, pre-prasugrel PR in the upper quartile (313 PRU) was the only independent factor associated with HPR under prasugrel MD. In contrast, pre-prasugrel PR in the lower quartile (242 PRU) and prasugrel loading emerged as the only independent predictors of HPI. In patients under different clinical settings receiving prasugrel 10 mg MD a significant amount of the PR variability in response to prasugrel may be explained by pre- treatment PR level, ACS, prasugrel loading and smoking status. A high pre- treatment PR is associated with HPR, while a low pre-treatment PR and prasugrel loading predict HPI.

Brief hyperventilation is occasionally accompanied by repolarization abnormalities in subjects without apparent heart disease. However, the effect of prolonged hyperventilation on repolarization abnormalities is not clearly defined. We analysed the repolarization abnormalities induced by prolonged hyperventilation, correlated with hyperventilation induced haemodynamic changes and exercise test results and assessed the effect on them of age, gender, smoking and hypertension. Prolonged hyperventilation (overbreathing at least 30 respirations/min for 5 min and 10 min recovery) was performed in 474 healthy volunteers (269 men, 205 women) 42.6 +/- 13.5 years old. The electrocardiogram was analysed for transient ST depression or T-wave inversion. Repolarization abnormalities were observed in 72 subjects, 47 men (17.5%) and 25 women (12.2%). Age, gender, smoking and hypertension did not influence the overall incidence of repolarization abnormalities. ST depression was more frequently observed in women (4.4 vs 0.7%, P < 0.01), while T wave inversion from negative to positive was more frequent in men (8.9 vs 2.4%, P < 0.006). All subjects with ST depression were non-smokers (4.1% of the non-smokers, P < 0.003 compared to smokers). Repolarization abnormalities occurred usually (80.5%), but not exclusively, within the first hyperventilation minute. Subjects with repolarization abnormalities developed higher heart rate change with hyperventilation than those without repolarization abnormalities (29.2 +/- 13.1 vs 24.2 +/- 12.7, P < 0.002). A positive exercise test was observed in 45.4% of subjects with hyperventilation induced ST depression but only in 13.1% of subjects with T-wave changes, P < 0.02. Repolarization abnormalities are not uncommon during prolonged hyperventilation. Hear rate change affects the occurrence of repolarization abnormalities, while gender and smoking influence the type of repolarization abnormalities. ST depression but not T-wave inversion during hyperventilation is associated with a positive exercise test. Increased understanding about hyperventilation-induced repolarization abnormalities could affect use of the method in the clinic, either as a provocation test or as a complement to the interpretation of the exercise test.

Nicholas G. Kounis *, George D. Soufras , George N. Kounis , George Hahalis c Department of Medical Sciences, Patras Highest Institute of Education and Technology, Patras, Achaia, Greece Department of Cardiology, ‘‘Saint Andrews’’ State General Hospital, Patras, Achaia, Greece Department of Cardiology, University of Patras Medical School, Patras, Achaia, Greece

Specific aim: We have previously shown that platelets from patients with myocardial infarction (with ST elevation-STEMI) can activate T cells in vitro. In this study we wanted to expand our initial observation and explore the mechanism of this T cell activation. Methods: After written informed consent was obtained, peripheral blood mononuclear cells (PBMCs) were isolated from heparinized venous blood obtained from 30 patients with STEMI (28 men and 2 women) at the time of hospital admission at diagnosis, before receiving any treatment, as well as 5 days and 30 days later. We also analyzed 15 healthy subjects (12 men and 3 women), and 7 patients with unstable angina who served as the disease control group. PBMCs were analyzed by flow cytometry with the following markers and their isotypic controls: CD4, CD25, CD127, FOXP3, and CD69. We also isolated platelet rich plasma or plasma alone from the patients and the healthy subjects, and used in mixed cultures with PBMCs. miR 155 levels were examined with real-time PCR. Results: Initially, we incubated T cells with platelets from patients with STEMI and examined T cell activation by CD69 expression. These T cells showed increased expression of CD69 compared to T cells treated with platelets from healthy subjects (p Next, the percentages of CD4+CD25+hi CD127low FOXP3+ (regulatory T cells, Tregs) were examined in all study subjects. Patients at presentation showed comparable Treg levels with the controls (healthy subjects and disease control group). Five days later, patients with STEMI displayed increased levels of Tregs compared with the controls (p Conclusion: Herein, we show that platelets from patients with STEMI can activate T cells in vitro. This platelet activation in patients with STEMI, results in an increase in Tregs through down-regulation of miR155, that return to normal levels a month later. This Treg increase reflects possibly an effort to suppress immune system activation secondary to platelet activation, shortly after the infarct. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

Variation in coronary/aortic (Pd/Pa) pressure ratio during standard (140mg/kg/min) adenosine infusion has been partially attributed to failure to achieve or preserve maximal hyperemia. We hypothesized that a higher dose (200μg/kg /min) of adenosine infusion may decrease Pd/Pa variation In a

Introduction In patients with ST elevation myocardial infarction (STEMI) increased platelet reactivity has been described to affect the primary percutanuous coronary intervention (PPCI) outcome. We aimed to evaluate the predictive accuracy of intrinsic platelet reactivity for intracoronary thrombus burden in P2Y12 inhibitor- naive STEMI patients. Patients and Methods In a prospective, observational, cohort study we enrolled 94 consecutive STEMI patients undergoing PPCI, subjected to platelet reactivity assessment prior to any P2Y12 blockade, with visible angiographic thrombus in the infarct related artery (stratified as Grade A, B and C). Platelet-function testing was performed with the VerifyNow point-of-care P2Y12 assay immediately prior to intervention. Results Intrinsic platelet reactivity was higher with greater thrombus burden: Grade A 158.8 ± 51.1 PRU, Grade B 217.4 ± 62.1 PRU and Grade C 243.4 ± 58.6 PRU, p = 0.009 and Spearman r = 0.32 (0.12-0.49 95% CI), p = 0.002. ROC analysis revealed an AUC = 0.7 (Standard error 0.07, p = 0.03). An intrinsic platelet reactivity value of > 220 PRU had 65% sensitivity (53–76 95%CI), 76% specificity (55–91 95%CI), 88% positive predictive value (76–96 95%CI) and 44% negative predictive value (29–60 95%CI) for detection of high thrombus burden. In multivariate analysis intrinsic platelet reactivity > 220 PRU emerged as an independent predictor of high thrombus burden (RR = 1.5, 1.15-2.07 95% CI, p = 0.004). Conclusions In patients admitted with STEMI the intrinsic platelet reactivity -as assessed by a point-of-care assay- is positively associated with the degree of intracoronary thrombus, while having a moderate accuracy in predicting high thrombus burden.

Cardiac events occur in 1% to 5% of patients undergoing non-cardiac surgery. Myocardial ischemia and nonfatal myocardial infarction constitute the most significant risk factors for mortality and cardiovascular morbidity, in patients with coronary artery disease. Perioperative b- blockade has been reported to reduce the risk of perioperative cardiac complications. Seven multicentre randomized trials have evaluated the impact of perioperative b-blocker administration on incidence of cardiovascular events.The Study of Perioperative Ischemia Research Group, the DECREASE and the BBSA trials focused on high risk patients for perioperative complications. The POBBLE, MaVS, and DIPOM trials did not target at patients with specific clinical risk factors, except DIPOM that included patients with diabetes. Finally, the POISE trial randomized patients with a wide variety of risk factors for perioperative cardiac complications. Interestingly, five meta-analyses reported a significant reduction in patients receiving b-blockers, with respect to perioperative myocardial ischemia and myocardial infarction. In conclusion, consistent evidence demonstrated a reduction in cardiac mortality and myocardial infarction by perioperative b-blockade in patients with clinical risk factors, undergoing high-risk non-cardiac surgery. However, patients with extensive preoperative ischemia were at high risk of perioperative cardiac complications, despite b-blocker therapy. Conversely, perioperative b-blocker therapy did not reduce the incidence of cardiac complications in patients without clinical risk factors. While, the safety and effectiveness of perioperative b-blockers in intermediate-risk patients, still remain a debatable issue.

The study aimed to compare the antiplatelet action of ticagrelor with prasugrel in acute coronary syndrome (ACS) patients with high on-treatment platelet reactivity (HTPR) while on clopidogrel after percutaneous coronary intervention (PCI).Newer P2Y12 inhibitors like prasugrel and ticagrelor provide stronger platelet inhibition compared with clopidogrel. Both agents are efficacious in patients with HTPR while on clopidogrel, but direct comparison between them has not yet been reported.In a prospective, single-center, single-blind study, 44 (of 139 screened, 31.7%) ACS patients with HTPR while on clopidogrel 24 h post-PCI were randomized to either ticagrelor 90 mg twice daily or prasugrel 10 mg once daily for 15 days with a crossover directly to the alternate treatment for another 15 days. HTPR was defined as platelet reactivity units (PRU) ≥ 235 as assessed by the VerifyNow P2Y12 function assay.The primary endpoint of platelet reactivity at the end of the 2 treatment periods was lower for ticagrelor (32.9 PRU, 95% confidence interval [CI]: 18.7 to 47.2) compared with prasugrel (101.3 PRU, 95% CI: 86.8 to 115.7) with a least squares mean difference of -68.3 PRU (95% CI: -88.6 to -48.1; p0.001). The secondary endpoint of HTPR rate was 0% for ticagrelor and 2.4% for prasugrel (1 of 42, p = 0.5). No patient exhibited a major bleeding event at either treatment group.In patients with ACS exhibiting HTPR while on clopidogrel 24 h post-PCI, ticagrelor produces a significantly higher platelet inhibition compared with prasugrel. (Ticagrelor Versus Prasugrel in Acute Coronary Syndromes After Percutaneous Coronary Intervention; NCT01360437).

Tryptase and chymase are unique mast cell proteases that are essential in atherogenesis. This study establishes a link between serum tryptase and chymase levels and human coronary heart diseases (CHD) in a cohort of 270 subjects. Serum tryptase levels were significantly higher in patients with substantial CHD than in those without substantial CHD (substantial CHD vs. unsubstantial CHD: 7.81± 0.52 vs. 6.11±0.51 ng/mL, P=0.002). After subgrouping the substantial CHD patients into those with acute myocardial infarction (AMI) and those with unstable or stable angina pectoris (UAP or SAP), we demonstrated that serum tryptase levels were nearly doubled in AMI patients as compared with unsubstantial CHD patients (11.13 ±1.55 vs. 6.11±0.51 ng/mL, P

The prevalence of prasugrel contraindications and specific conditions requiring precaution for its use in a real world acute coronary syndrome (ACS) population is not known. We performed a prospective descriptive study in 1016 consecutive moderate to high risk ACS patients. In 646 patients (63.6%) subjected to percutaneous coronary intervention, analysis of absolute contraindications (history of stroke/transient ischemic attack or active bleeding), relative contraindications and specific conditions (age ≥ 75 years and/or weight

High on-treatment platelet reactivity (HTPR) is present in a substantial percentage of patients on chronic clopidogrel treatment and may have prognostic implications. Strategies to optimize platelet inhibition in such patients are not clear.We performed a prospective, single-center, single-blinded, investigator-initiated randomized, crossover study of platelet inhibition by prasugrel 10 mg/day versus high-dose 150 mg/day clopidogrel, with a 14 day treatment period, in 31 patients with HTPR (out of 99 screened, 31.3%) while on chronic (≥ 12 months) treatment with clopidogrel. All patients had stable coronary artery disease and 87.1% of them had a prior percutaneous coronary intervention. Platelet reactivity (PR) was assessed by the VerifyNow assay measured in platelet reactivity units (PRU).The primary end point of PR at the end of the two treatment periods was lower in patients receiving prasugrel compared with high dose clopidogrel ( least squares estimate 148.1, 95% CI 127.1-169.2 and 219.8, 95% CI 198.6-240.9 respectively, P.001). The secondary end point of HTPR rate was lower for prasugrel compared with clopidogrel, 11.5% vs 46.3%, P = .003.Prasugrel appears more effective than double clopidogrel in inhibiting PR in patients with HTPR following chronic clopidogrel treatment.

Tissue coverage and strut apposition of drug eluting stents (DES), which can be assessed with optical coherence tomography (OCT), may be associated with late stent thrombosis (LST).Prospective observational angiographic and OCT follow-up at 6 months post-implantation of a biolimus-A9 eluting stent (BES) vs. a paclitaxel eluting stent (PES), with biodegradable polymer carriers. The primary outcome was the percent difference of uncovered struts between BESs and PESs.A maximum likelihood model was used for analysis, to account for data clustering. Sixteen patients were treated with BES (28 lesions/4530 struts) and 16 with PES (23 lesions/4450 struts). Overall, BESs compared to PESs had more uncovered [0.41% vs. 0.21%, difference estimate (DE) 0.2 (95% CI, 0.06-0.34), p=0.006], malapposed [0.18% vs. 0.04%, DE 0.14 (95% CI 0.05-0.23), p=0.003], uncovered and malapposed [0.08% vs. 0.026%, DE 0.057 (95% CI 0.015-0.1), p=0.01] and protruding struts [0.23% vs. 0.04%, DE 0.185 (95% CI 0.1-0.27), p0.001], and significantly lower neointimal thickness (59.3 ± 28.2 μm vs. 201.7 ± 97.5, p0.001). None of the BESs was totally covered with neointima, in contrast to 5 (21.7%) PESs (p=0.01). Thrombus was detected in 1 (3.6%) BES and 5 (21.7%) PESs (p=0.05); however, no patient experienced clinical stent thrombosis.Between two stents with biodegradable polymer, OCT demonstrated that BESs had more uncovered and malapposed struts compared to PESs at 6 months. This difference might be partly attributed to the more potent antiproliferative properties of biolimus-A9; however, its impact on clinical outcome and on the risk of LST is yet to be determined.

Background The impact of stent restenosis, stent thrombosis, or progression of disease at another site as responsible mechanisms of acute myocardial infarction (AMI) after stent implantation is not clear. Methods By searching our catheterization laboratory database for a 4-year period, 91 cases of nonfatal AMI at least 1 month after stent implantation (32.6% drug-eluting stents) were identified. By detailed comparison of post-AMI with the initial percutaneous coronary intervention angiogram, the mechanism of AMI was analyzed. Results Acute myocardial infarction was attributed to disease progression at another site in 42 (46.2%), stent restenosis in 35 (38.4%), and stent thrombosis in 10 (11%) cases. The AMI mechanism could be either stent related or disease progression (nonidentifiable culprit lesion) in 4 cases (4.4%). The median time from percutaneous coronary intervention to AMI was 27, 19, and 9 months for disease progression at another site, restenosis, and stent thrombosis group, respectively ( P = .03). ST-elevation myocardial infarction occurred in 38.1% of the disease progression, in 20% of the restenosis, and in 60% of the stent thrombosis cases ( P = .046). Conclusions In a "real world" population, late after stent implantation, a patient has an almost equal probability to have suffered a nonfatal AMI from either stent restenosis/thrombosis or disease progression at another site. Continuous research efforts are necessary to equally address both stent therapy and disease progression.