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The early detection of coronary artery disease in patients with type 2 diabetes mellitus remains uncertain. The aim of the study was to explore the correlation of circulating biomarkers for inflammation Interleukin-6 (IL-6), high-sensitivity C-reactive protein (hs-CRP) as well as N-terminal pro

Objectives This study sought to evaluate the feasibility and safety of autologous bone marrow-derived and cardiogenically oriented mesenchymal stem cell therapy and to probe for signs of efficacy in patients with chronic heart failure. Background In pre-clinical heart failure models, cardiopoietic stem cell therapy improves left ventricular function and blunts pathological remodeling. Methods The C-CURE (Cardiopoietic stem Cell therapy in heart failURE) trial, a prospective, multicenter, randomized trial, was conducted in patients with heart failure of ischemic origin who received standard of care or standard of care plus lineage-specified stem cells. In the cell therapy arm, bone marrow was harvested and isolated mesenchymal stem cells were exposed to a cardiogenic cocktail. Derived cardiopoietic stem cells, meeting release criteria under Good Manufacturing Practice, were delivered by endomyocardial injections guided by left ventricular electromechanical mapping. Data acquisition and analysis were performed in blinded fashion. The primary endpoint was feasibility/safety at 2-year follow-up. Secondary endpoints included cardiac structure/function and measures of global clinical performance 6 months post-therapy. Results Mesenchymal stem cell cocktail-based priming was achieved for each patient with the dose attained in 75% and delivery without complications in 100% of cases. There was no evidence of increased cardiac or systemic toxicity induced by cardiopoietic cell therapy. Left ventricular ejection fraction was improved by cell therapy (from 27.5 +/- 1.0% to 34.5 +/- 1.1%) versus standard of care alone (from 27.8 +/- 2.0% to 28.0 +/- 1.8%, p < 0.0001) and was associated with a reduction in left ventricular end-systolic volume (-24.8 +/- 3.0 ml vs. -8.8 +/- 3.9 ml, p < 0.001). Cell therapy also improved the 6-min walk distance (+62 +/- 18 m vs. -15 +/- 20 m, p < 0.01) and provided a superior composite clinical score encompassing cardiac parameters in tandem with New York Heart Association functional class, quality of life, physical performance, hospitalization, and event-free survival. Conclusions The C-CURE trial implements the paradigm of lineage guidance in cell therapy. Cardiopoietic stem cell therapy was found feasible and safe with signs of benefit in chronic heart failure, meriting definitive clinical evaluation. (C-Cure Clinical Trial; NCT00810238) (C) 2013 by the American College of Cardiology Foundation

Objectives The purpose of this study was to compare 600- and 300-mg clopidogrel loading doses in patients with ST-segment elevation myocardial infarction (STEMI). Background Given the high thrombotic risk of patients with STEMI, greater platelet inhibition may improve outcome in those patients receiving percutaneous coronary intervention (PCI). Although observational data suggest that pretreatment with a 600-mg clopidogrel loading dose may be more effective than the 300-mg regimen in primary PCI, this hypothesis has never been tested in a randomized study. Methods A total of 201 patients undergoing primary PCI for STEMI randomly received a 600-mg (n = 103) or 300-mg (n = 98) clopidogrel loading dose before the procedure. The primary endpoint was the evaluation of the infarct size, defined as the area under the curve of cardiac markers. Results Infarct size was significantly lower in the high-dose regimen: median creatine kinase-myocardial band 2,070 ng/ml (interquartile range [IQR]: 815 to 2,847 ng/ml) versus 3,049 ng/ml (IQR: 1,050 to 7,031 ng/ml) in the 300-mg group, p = 0.0001; troponin-I 255 ng/ml (IQR: 130 to 461 ng/ml) versus 380 ng/ml (IQR: 134 to 1,406 ng/ml), p Conclusions In STEMI patients, pre-treatment with a 600-mg clopidogrel loading dose before primary PCI was associated with a reduction of the infarct size compared with a 300-mg loading dose, as well as with improvement of angiographic results, residual cardiac function, and 30-day major adverse cardiovascular events; further studies are warranted to evaluate impact of such strategy on survival.

We appreciate the interest of Dr. Mielewczik and colleagues in the C-CURE (Cardiopoietic stem Cell therapy in heart failURE) trial. As outlined in our paper [(1)][1], feasibility and safety were the primary endpoints in this first-in-man study that assessed cardiogenically-oriented, autologous bone

ObjectivesThe aim of our study was to compare coronary vasomotion after implantation of a second-generation biolimus A9-eluting stent (BES) and of a sirolimus-eluting stent (SES).BackgroundDrug-eluting stents (DES) have been associated with impaired local coronary vasomotion, delayed endothelialization, and increased late thrombotic risk. New DES with different drugs, pharmacokinetics, and polymers have been developed.MethodsNineteen patients with a BES and 15 patients with a SES were studied 9 months after stent implantation. Endothelium-dependent and -independent coronary vasomotion were tested proximally and distally to the stent as well as at a reference segment during right atrial pacing at increasing heart rates. Quantitative coronary angiographic measurements were performed offline.ResultsOf the patients with BES, 2 showed vasoconstriction with increased heart rate and 17 showed vasodilatation. Of the patients with a SES, 9 showed vasoconstriction while 6 showed vasodilatation. The SES showed significant vasoconstriction at both the proximal (−2.3 ± 10% vs. 7.9 ± 10%) and the distal (−5.4 ± 9% vs. 6.1 ± 8%) segments to the stent compared with the BES (p = 0.003 for proximal, p < 0.001 for distal segment). Endothelium-independent vasomotion after intracoronary nitrates did not differ significantly between the 2 groups (p = NS for proximal and distal segment).ConclusionsUnlike the case with the SES, endothelium-dependent vasomotion at adjacent stent segments seems to be preserved after BES implantation. This result may be explained by the different drug release kinetics, DES design, or characteristics of polymer used in the stent system.

This study sought to evaluate the feasibility and safety of autologous bone marrow-derived and cardiogenically oriented mesenchymal stem cell therapy and to probe for signs of efficacy in patients with chronic heart failure.In pre-clinical heart failure models, cardiopoietic stem cell therapy improves left ventricular function and blunts pathological remodeling.The C-CURE (Cardiopoietic stem Cell therapy in heart failURE) trial, a prospective, multicenter, randomized trial, was conducted in patients with heart failure of ischemic origin who received standard of care or standard of care plus lineage-specified stem cells. In the cell therapy arm, bone marrow was harvested and isolated mesenchymal stem cells were exposed to a cardiogenic cocktail. Derived cardiopoietic stem cells, meeting release criteria under Good Manufacturing Practice, were delivered by endomyocardial injections guided by left ventricular electromechanical mapping. Data acquisition and analysis were performed in blinded fashion. The primary endpoint was feasibility/safety at 2-year follow-up. Secondary endpoints included cardiac structure/function and measures of global clinical performance 6 months post-therapy.Mesenchymal stem cell cocktail-based priming was achieved for each patient with the dose attained in 75% and delivery without complications in 100% of cases. There was no evidence of increased cardiac or systemic toxicity induced by cardiopoietic cell therapy. Left ventricular ejection fraction was improved by cell therapy (from 27.5 ± 1.0% to 34.5 ± 1.1%) versus standard of care alone (from 27.8 ± 2.0% to 28.0 ± 1.8%, p 0.0001) and was associated with a reduction in left ventricular end-systolic volume (-24.8 ± 3.0 ml vs. -8.8 ± 3.9 ml, p 0.001). Cell therapy also improved the 6-min walk distance (+62 ± 18 m vs. -15 ± 20 m, p 0.01) and provided a superior composite clinical score encompassing cardiac parameters in tandem with New York Heart Association functional class, quality of life, physical performance, hospitalization, and event-free survival.The C-CURE trial implements the paradigm of lineage guidance in cell therapy. Cardiopoietic stem cell therapy was found feasible and safe with signs of benefit in chronic heart failure, meriting definitive clinical evaluation. (C-Cure Clinical Trial; NCT00810238).

The purpose of this study was to compare 600- and 300-mg clopidogrel loading doses in patients with ST-segment elevation myocardial infarction (STEMI).Given the high thrombotic risk of patients with STEMI, greater platelet inhibition may improve outcome in those patients receiving percutaneous coronary intervention (PCI). Although observational data suggest that pretreatment with a 600-mg clopidogrel loading dose may be more effective than the 300-mg regimen in primary PCI, this hypothesis has never been tested in a randomized study.A total of 201 patients undergoing primary PCI for STEMI randomly received a 600-mg (n = 103) or 300-mg (n = 98) clopidogrel loading dose before the procedure. The primary endpoint was the evaluation of the infarct size, defined as the area under the curve of cardiac markers.Infarct size was significantly lower in the high-dose regimen: median creatine kinase-myocardial band 2,070 ng/ml (interquartile range [IQR]: 815 to 2,847 ng/ml) versus 3,049 ng/ml (IQR: 1,050 to 7,031 ng/ml) in the 300-mg group, p = 0.0001; troponin-I 255 ng/ml (IQR: 130 to 461 ng/ml) versus 380 ng/ml (IQR: 134 to 1,406 ng/ml), p0.0001. In the 600-mg arm, Thrombolysis In Myocardial Infarction flow grade3 after PCI was less frequent (5.8% vs. 16.3%, p = 0.031), left ventricular ejection fraction at discharge was improved (52.1 ± 9.5% vs. 48.8 ± 11.3%, p = 0.026), 30-day major adverse cardiovascular events were fewer (5.8% vs. 15%, p = 0.049), and bleeding/entry site complications were not increased (secondary endpoints).In STEMI patients, pre-treatment with a 600-mg clopidogrel loading dose before primary PCI was associated with a reduction of the infarct size compared with a 300-mg loading dose, as well as with improvement of angiographic results, residual cardiac function, and 30-day major adverse cardiovascular events; further studies are warranted to evaluate impact of such strategy on survival.

[Figure][1] [![Graphic][3] ][3][![Graphic][4] ][4] A 49-year-old woman presented to the emergency department with dyspnea 3 days after her mother's death. The electrocardiogram at admission showed sinus tachycardia, T-wave inversion in leads V1through V3, and R/S >1 in leads

OBJECTIVESThe aim of this study was to analyze, in the same group of patients, the relationship between multiple variables of coronary lesion and results of exercise, dobutamine and dipyridamole stress echocardiography tests.BACKGROUNDIntegrated evaluation of the relation between stress echocardiography results and angiographic variables should include not only the assessment of stenosis severity but also evaluation of other quantitative and qualitative features of coronary stenosis.METHODSStudy population consisted of 168 (138 male, 30 female, mean age 51 ± 9 years) patients, on whom exercise (Bruce treadmill protocol), dobutamine (up to 40 mcg/kg/min) and dipyridamole (0.84 mg/kg over 10 min) stress echocardiography tests were performed. Stress echocardiography test was considered positive for myocardial ischemia when a new wall motion abnormality was observed. One-vessel coronary stenosis ranging from mild stenosis to complete obstruction of the vessel was present in 153 patients, and 15 patients had normal coronary arteries. The observed angiographic variables included particular coronary vessel, stenosis location, the presence of collaterals, plaque morphology according to Ambrose classification, percent diameter stenosis and obstruction diameter as assessed by quantitative coronary arteriography.RESULTSCovariates significantly associated with the results of physical and pharmacological stress tests included for all three stress modalities presence of collateral circulation, percent diameter stenosis and obstruction diameter, as well as lesion morphology (p < 0.05 for all, except collaterals for dobutamine stress test, p = 0.06). By stepwise multiple logistic regression analysis, the strongest predictor of the outcome of exercise echocardiography test was only percent diameter stenosis (p = 0.0002). However, both dobutamine and particularly dipyridamole stress echocardiography results were associated not only with stenosis severity - percent diameter stenosis (dobutamine, p = 0.04; dipyridamole, p = 0.003) - but also, and even more strongly, with lesion morphology (dobutamine, p = 0.006; dipyridamole, p = 0.0009). As all of stress echocardiography results were significantly associated with percent diameter stenosis, the best angiographic cutoff in relation to the results of stress echocardiography test was: exercise, 54%; dobutamine, 58% and dipyridamole, 60% (p < 0.05 vs. exercise).CONCLUSIONSIntegrated evaluation of angiographic variables have shown that the results of dobutamine and dipyridamole stress echocardiography are not only influenced by stenosis severity but also, and even more importantly, by plaque morphology. The results of exercise stress echocardiography, although separately influenced by plaque morphology, are predominantly influenced by stenosis severity, due to a stronger exercise capacity in provoking myocardial ischemia in milder forms of coronary stenosis.

ObjectivesThe aim of this study was to assess the tolerability and incremental diagnostic value of high adenosine doses in stress echocardiography testing in patients with coronary artery disease (CAD).BackgroundIn comparison with other pharmacologic stress echocardiography tests, standard dose adenosine stress has suboptimal sensitivity for detecting milder forms of CAD.MethodsAdenosine stress echocardiography was performed in 58 patients using a starting dose of 100mg/kg body weight per min over 3 min followed by 140mg/kg per min over 4 min (standard dose). If no new wall motion abnormality appeared, the dose was increased to 200mg/kg per min over 4 min (high dose). All patients underwent coronary angiography. Significant CAD was defined as >50% diameter stenosis in at least one major coronary artery. Thirty-three patients had one-vessel and seven had multivessel CAD. Coronary angiographic findings were normal in 18 patients.ResultsThe high adenosine dose caused a slight but significant increase over baseline values in rate-pressure product. Limiting side effects occurred in two patients during the standard dose protocol and in one patient receiving the high dose regimen. The test was stopped in 30 patients after the standard adenosine dose regimen because of a provoked new wall motion abnormality. The sensitivity of adenosine echocardiography with the standard dose was 75% (95% confidence interval [CI] 63% to 87%). After completion of the standard dose protocol, 28 patients continued testing with the high dose adenosine protocol. The overall sensitivity of adenosine echocardiography, calculated as cumulative, increased to 92% (95% CI 84% to 100%) with the high dose (p

Cardiac catheterization techniques deal with large amount of image data from which quantitative parameters are extracted. Our program provides relational database organization and management functions for both images and measurement data. In addition, it integrates database with our previously developed image analysis programs for intravascular ultrasound (IVUS) and coronary angiography. The program runs in Microsoft Windows environment and does not require specialized imaging hardware. Program consists of three functional modules: image database system, IVUS contour extraction/analysis module and coronary angiography contour extraction/analysis module, Image database system provides image retrieval, storage and display together with extracted quantitative data. Each database record includes data on patient administration, medical history and noninvasive test results. User is provided with browse and search controls for database navigation, as well as with query by example and lists and reports generation. Analysis programs are incorporated into the database through OLE (Object Linking and Embedding) technique, which enables user to launch appropriate image analysis program simply by clicking the mouse over the chosen image. Extracted analysis data are automatically stored in the appropriate database record. Furthermore, any other image processing/analysis Windows program that supports OLE and can act as OLE server may be linked with the database by simple Clipboard cut and paste operations. All images and data can be exported to other Windows applications (text processors, spreadsheets, statistical and data presentation software). In practical testing the program proved to be user friendly, interactive and flexible. It was particularly useful for integration of both images and quantitative data obtained by coronary angiography and by IVUS, being helpful in the validation of the latter technique, and providing better insight into the extent and severity of coronary arteriosclerotic disease.

The role of myocardial catecholamine concentration (MCC) in diagnosis and outcome of primary heart muscle diseases (HMD) is still incompletely defined. To elucidate this problem we analyzed diagnostic utility of MCC measurements in pts with biopsy proven myocarditis (BPM), hypertrophic cardiomyopathy (HCM), and idiopathic dilated cardiomyopathy (DCM). as well as MCC prognostic impact in DCM. Our study group consisted of 86 pts, 20 of them with BPM (80% males, aged 18–42 yrs), 34 HCM pts (64% males, aged 29–54 yrs) and 32 pts with DCM (75% males, aged 21–56 yrs). At the initial assessment all pts underwent cardiac catheterization and endomyocardial biopsy (EMB). Myocardial norepinephrine (MNEC). epinephrine (MEC). and dopamine (MDC) concentrations were measured in EMB samples using catechol-O-methyl-transferase radioenzymatic method. Obtained values (ng/g of fresh myocardial tissue ft) are shown in the table below: MNEC MEC MDC BPM 415.4 ± 71.1 † 57.3 ± 48 † 76.6 ± 9.2 ns HCM 781.0 ± 125.1 ** 91.3 ± 13.1 ** 78.1 ± 9.3 ns DCM 262.2 ± 68.9 † 36.9 ± 7.1 ‡ 72.6 ± 12.1 ns † -p l 001 (BPM vs. DCM); ** -p l 001 (HCM vs. BPM); † -p l 0.01 (HCM vS. DCM). In addition, we analyzed the effect of MNEC and MEC on the five years survival of 31 DCM pts. Survival (18/31) was significantly better in pts with higher MNEC (411.8 ± 43.4 ng/g ft survivors vs. 278.5 ± 75.7 ng/g ft non-survivors, p l 0.01) and MEC (55.3 ± 4.5 ng/g ft survivors vs. 39.2 ± 9.3 ng/g ft non-survivors, p l 0.01). Univariate and multivariate analysis demonstrated that both MNEC and MEC predicted long-term survival independently and their low concentrations were associated with increased mortality. In conclusion, these data indicate that MCC measurements may be helpful as a complementary tool in diagnostic evaluation of pts with HMD. Furthermore, MNEC and MEC should be considered as valuable prognostic markers of the long-term survival of DCM pts.

Objectives. This study was designed to assess the clinical, hemodynamic and diagnostic effects of the addition of dobutamine to dipyridamole echocardiography. Background. Pharmacologic stress echocardiography with either dipyridamole or dobutamine has gained acceptance because of its safety, feasibility, diagnostic accuracy and prognostic power. The main limitation of the two tests is a less than ideal sensitivity in some patient subsets, such as those with limited coronary artery disease. We hypothesized that two pharmacologic stresses might act synergistically in the induction of ischemia by combining the mechanisms of inappropriate coronary vasodilation (with dipyridamole) and an increase in myocardial oxygen consumption (with dobutamine). Methods. One hundred fifty patients (mean [±SD] age 51 ± 11 years) referred for stress echocardiography were initially studied by dipyridamole-dobutamine echocardiography. The test was stopped during the dipyridamole step in 95 patients for achievement of a predetermined end point (obvious dyssynergy induced by lower or higher dipyridamole dose), and dipyridamoledobutamine tests were performed in 55 patients (negative dipyridamole echocardiographic test). In the same 150 patients the dobutamine echocardiographic test (up to 40 μg/kg body weight per min) was performed on a separate day. Results. Significant coronary artery disease (>50% diameter stenosis of at least one major coronary vessel by quantitative coronary arteriography) was present in 131 patients (one vessel in 115; two vessels in 10, three vessels in 6), with normal coronary arteriography in 19. The feasibility of the dipyridamoledobutamine test was 96%. Self-limiting side effects occurred in 5% of patients. The peak rate-pressure product was lowest during the dipyridamole test (132 ± 30) and was comparable during the dobutamine (186 ± 59) and dipyridamole-dobutamine tests (179 ± 45, p = NS vs. dobutamine; p < 0.01 vs. dipyridamole). Sensitivity was 71% for dipyridamole, 75% for dobutamine and 92% for dipyridamole-dobutamine echocardiography (dipyridamole vs. dipyridamole-dobutamine, p < 0.01; dobutamine vs. dipyridamole-dobutamine, p < 0.01; dipyridamole vs. dobutamine, p = NS), whereas specificity was 89% for dipyridamole, 79% for dobutamine and 89% for dipyridamole-dobutamine echocardiography (p = NS for all). Conclusions. Routine dobutamine addition to dipyridamole stress testing is clinically useful and well tolerated. It expands the spectrum of the disease detectable by pharmacologic stress echocardiography and allows documentation of milder forms of coronary artery disease that can be missed by conventional dipyridamole or dobutamine stress echocardiography.

Objectives. We sought to evaluate the effects of combined administration of infra-low dose dipyridamole and low dose dobutamine on assessment of myocardial viability. Background. Low dose pharmacologic stress echocardiography with either dobutamine or dipyridamolc infusion has been proposed for the recognition of myocardial viability. Methods. Thirty-four patients with rest wall motion dyssynergy by two-dimensional echocardiography and with angiographically proved coronary artery disease underwent in combination with two-dimensional echocardiographic monitoring: 1) low dose (5 to 10 μg/kg per min over 3 min) dobutamine infusion; 2) infra-low dose (0.28 mg/kg over 4 min) dipyridamole infusion; 3) combination of infra-low dose dipyridamole infusion immediately followed by low dose dobutamine infusion (combined dipyridamole-dobutamine). Results. Follow-up rest echocardiography was available in 30 patients. After revascularization, 82 segments showed a contractile improvement of ≥1 grade, whereas 63 segments remained unchanged. The sensitivity of dobutamine, dipyridamole and combined dipyridamole-dobutamine for predicting recovery was 72% (95% confidence interval [CI] 60.9% to 81.3%), 67% (CI 55.8% to 77%) and 94% (CI 86.3% to 97.9%), respectively. The specificity of dipyridamole, dobutamine and combined dipyridamole-dobutamine was 95% (CI 86.7% to 99%), 92% (CI 82.4% to 97.3%) and 89% (CI 78.4% to 95.4%), respectively. The accuracy of the dobutamine, dipyridamole and combined dipyridamole-dobutamine test was 80%, 79% and 92%, respectively (combined dipyridamole-dobutamine vs. dobutamine, p < 0.05; combined dipyridamole-dobutamine vs. dipyridamole, p < 0.01). Conclusions. Infra-low dose dipyridamole added to low dose dobutamine recruits an inotropic reserve in asynergic segments that were nonresponders after either dobutamine or dipyridamole alone and destined to recover after revascularization.

Background: Current STEMI guideline recommendations limit the use of prasugrel to clopidogrel-naïve patients. However, in daily clinical practice a considerable proportion of STEMI patients undergoing primary PCI are preloaded with clopidogrel. Whether the use of prasugrel in clopidogrel pretreated STEMI patients is safe remains unknown. Similarly, the efficacy of a combined loading dose regimen has not been evaluated. Methods: Between 1 September 2009 and 15 October 2012, a total of 1,157 STEMI patients were included in the randomized COMFORTABLE AMI trial (NCT 00962416) and 891 STEMI patients in the SPUM ACS registry (NCT 01000701) at 12 centers. Patients were divided into three groups according to type of peri-procedural antiplatelet loading: (1) Clopidogrel and subsequent Prasugrel loading dose [CP], (2) Prasugrel loading dose alone [P] (3) Clopidogrel loading dose alone [C]; 23 patients were excluded because they were not exposed to Clopidogrel and Prasugrel. The primary safety endpoint was the rate of BARC type 3, 4 and 5 bleeding at 30 days. The primary efficacy endpoint was the composite of cardiac death, nonfatal MI and nonfatal stroke at 30 days. Outcomes were analyzed using Cox's Regressions (crude) and multinomial ITPW weighted Cox's Regressions. Results: A total of 2,025 patients were analysed of whom 428 (21.1%) had received CP, 447 (22.1%) patients P alone, and 1,150 (56.8%) patients C alone. The primary safety endpoint was observed among 1.2% of CP, 1.6% of P, and 1.5% of C patients (CP vs C ad. HR 0.99 (0.36-2.72), PC vs P ad. HR 0.73 (0.22-2.41). The primary safety endpoint occurred less frequently among CP (1.9%) compared with C patients (5.0%, adjusted HR 0.47 (0.22-1.00), but with similar frequency among P and C patients (2.9% vs 5.0%, ad. HR 0.68 (0.27-1.73). The net clinical benefit outcome parameter tended to be lower among CP (2.8%) compared with C patients (6.3%, ad. HR 0.56 (0.30-1.05), whereas no significant difference was observed between P and C patients (3.8% vs 6.3%, ad. HR 0.85 (0.39-1.86). Conclusions: Among STEMI patients preloaded with Clopidogrel, the concurrent administration of a Prasugrel loading dose appears safe and potentially more effective than Clopiogrel alone.