Ticagrelor induced systemic inflammatory response syndrome.

BACKGROUND: Ticagrelor is a reversible and direct-acting oral antagonist of the adenosine diphosphate receptor P2Y12. Possible adenosine-mediated effects of ticagrelor on inflammation are complex and incompletely understood. To our knowledge, ticagrelor-induced systemic inflammatory response syndrome (SIRS) has not yet been described. CASE PRESENTATION: We report the case of an 84 years old patient presenting with SIRS subsequent to initiation of ticagrelor after implantation of two drug eluting stents. A broad diagnostic work-up for alternative causes and therapeutic measures were unrevealing. Discontinuation of the agent was followed by rapid improvement in clinical and laboratory signs of SIRS. CONCLUSIONS: After exclusion of other causes, ticagrelor needs to be considered as a possible causative agent for SIRS. Due to the widespread use of ticagrelor, clinicians should be aware of this possible adverse drug reaction.

Cardiovascular magnetic resonance imaging for diagnosis and clinical management of suspected cardiac masses and tumours.

AIMS: To evaluate the diagnostic accuracy of cardiovascular magnetic resonance (CMR) imaging from a risk-stratification and therapeutic-management perspective in patients with suspected cardiac tumours. METHODS AND RESULTS: Cardiovascular magnetic resonance exams of 41 consecutive patients (aged 61 ± 14 years, 21 men) referred for evaluation of a suspected cardiac mass were reviewed for tumour morphology and signal characteristics in various unenhanced and contrast-enhanced sequences. Cardiovascular magnetic resonance-derived diagnosis and treatment were compared with clinical outcome and histology in patients undergoing surgery or autopsy (n = 20). In 18 of 41 patients, CMR excluded masses or reclassified them as normal variants; all were treated conservatively. In 23 of 41 patients, CMR diagnosed a neoplasm (14 'benign', 8 'malignant', and 1 'equivocal'); 18 of these patients were operated on, 2 managed conservatively, and 3 by palliation. During follow-up of 705 (inter-quartile range 303-1472) days, 13 patients died. No tumour-related deaths occurred in conservatively managed patients. Patients with a CMR-based diagnosis and treatment of benign tumour had a similar survival as patients without detectable tumour. Compared with histology, CMR correctly classified masses as 'benign or malignant' in 95% of the cases. Tumour perfusion, invasiveness, localization, and pericardial fluid were valuable to distinguish between malignant and benign tumours. Soft tissue contrast and signal intensity patterns in various sequences were valuable for excluding neoplastic lesions and helped to obtain tissue characterization at the histological level in selected tumour cases, respectively. CONCLUSION: Comprehensive CMR provides a confident risk-stratification and clinical-management tool in patients with suspected tumours. Patients where CMR excludes tumours can be managed conservatively.

Copeptin and risk stratification in patients with acute dyspnea.

INTRODUCTION: The identification of patients at highest risk for adverse outcome who are presenting with acute dyspnea to the emergency department remains a challenge. This study investigates the prognostic value of Copeptin, the C-terminal part of the vasopressin prohormone alone and combined to N-terminal pro B-type natriuretic peptide (NT-proBNP) in patients with acute dyspnea. METHODS: We conducted a prospective, observational cohort study in the emergency department of a university hospital and enrolled 287 patients with acute dyspnea. RESULTS: Copeptin levels were elevated in non-survivors (n = 29) compared to survivors at 30 days (108 pmol/l, interquartile range (IQR) 37 to 197 pmol/l) vs. 18 pmol/l, IQR 7 to 43 pmol/l; P < 0.0001). The areas under the receiver operating characteristic curve (AUC) to predict 30-day mortality were 0.83 (95% confidence interval (CI) 0.76 to 0.90), 0.76 (95% CI 0.67 to 0.84) and 0.63 (95% CI 0.53 to 0.74) for Copeptin, NT-proBNP and BNP, respectively (Copeptin vs. NTproBNP P = 0.21; Copeptin vs. BNP P = 0.002). When adjusted for common cardiovascular risk factors and NT-proBNP, Copeptin was the strongest independent predictor for short-term mortality in all patients (HR 3.88 (1.94 to 7.77); P < 0.001) and especially in patients with acute decompensated heart failure (ADHF) (HR 5.99 (2.55 to 14.07); P < 0.0001). With the inclusion of Copeptin to the adjusted model including NTproBNP, the net reclassification improvement (NRI) was 0.37 (P < 0.001). An additional 30% of those who experienced events were reclassified as high risk, and an additional 26% without events were reclassified as low risk. CONCLUSIONS: Copeptin is a new promising prognostic marker for short-term mortality independently and additive to natriuretic peptide levels in patients with acute dyspnea.

Routine echocardiography after radiofrequency ablation: to flog a dead horse?

AIMS: Radiofrequency ablation (RFA) is frequently used to treat sustained arrhythmias. One major complication is pericardial effusion-tamponade. Therefore, many centres perform echocardiography after interventions, but data on necessity of such routine procedures are scarce. METHODS AND RESULTS: We included 510 patients with RFA and compared echocardiographic results acquired before and <24 h after intervention. We defined pericardial effusion as 'small', if <10 mm in diastole, 'moderate' if >10 mm, 'large' if >20 mm, or tamponade (>20 mm with haemodynamic compromise). Age was 55 +/- 16 years, 40% were females. Thirty-five percentage underwent RFA for atrioventricular nodal re-entrant tachycardia (AVNRT), 28% for atrial flutter, 15% for atrial fibrillation (AF), 12% for Wolff-Parkinson-White (WPW) syndrome, and 10% for different other arrhythmias. In 16 patients (3.2%), small asymptomatic effusions were detected. The only moderate effusion was suspected due to procedure circumstances. Radiofrequency ablation for AF had a higher incidence compared to AVNRT and flutter (P = 0.001 and <0.0001, respectively) or to WPW syndrome (P = 0.06). CONCLUSION: Numbers of significant pericardial effusion as detected by routine echocardiography were low (3.6%) and clinically relevant effusions absent. We thus recommend performing echocardiography after RFA only, if effusion is suspected clinically or if RFA was performed for AF, due to the high incidence of effusions with this type of ablation.

Drug-eluting stents compared with bare metal stents improve late outcome after saphenous vein graft but not after large native vessel interventions.

OBJECTIVES: To define long-term efficacy of different stent types in saphenous vein graft (SVG) interventions. METHODS: In BASKET (Basel Stent Cost Effectiveness Trial), major adverse cardiac events (MACE), i.e. cardiac death, myocardial infarction and symptom-driven target vessel revascularization (TVR) were assessed after 18 months comparing drug-eluting stents (DES) versus bare metal stents (BMS), and SVG and large native vessels (> or =3.0 mm). RESULTS: Large vessel interventions were performed in 605 patients. Patients with SVG interventions (n = 47, 8%) were older and had more often hypertension, prior myocardial infarction, prior revascularization and multivessel disease and less frequent ST-elevation myocardial infarction than patients with large native vessel interventions (n = 558, 92%). Stent number and length were higher in SVG than in large native vessel interventions. Baseline characteristics were similar for DES and BMS. In SVG stenting, long-term outcome was better in DES- than in BMS-treated patients (MACE 21 vs. 62%, p = 0.007, mainly due to TVR 18 vs. 46%, p = 0.045), but for large native vessel stenting, no significant difference was noted (MACE: 13 vs. 16%, p = 0.40). CONCLUSIONS: Among patients with SVG disease, treatment with DES resulted in a better long-term outcome than treatment with BMS. In contrast, no DES benefit was found in similarly sized native vessels regarding MACE.

[Noninvasive diagnostic of coronary artery disease]. / Die nichtinvasive Bilddiagnostik der koronaren Herzkrankheit.

Noninvasive imaging of coronary artery disease has extensively evolved during the last decade. Today, at least four imaging techniques with excellent image quality such as echocardiography, myocardial perfusion scintigraphy and PET, cardiac magnetic resonance and cardiac CT are widely available in order to estimate the risk for future ischemic events, to corroborate the suspected diagnosis of coronary artery disease, to demonstrate the extent and localisation of myocardial ischemia, to diagnose myocardial infarction and measure it's size, to identify the myocardium at risk during acute ischemia, to differentiate between viable and nonviable myocardium and thereby provide the basis for indications of revascularisations, to follow revascularized patients over long time, to assess the risk for sudden cardiac death and the development of heart failure after myocardial infarction and to depict atheromatosis and atherosclerosis of the coronary artery tree. Echocardiography is the most widely used imaging method in cardiology. It provides excellent information on morphology and function of nearly all cardiac structures. Stress echocardiography has been proven to be a reliable tool for the demonstration of myocardial ischemia and for the acquisition of prognostic data. Newer ultrasound techniques may further improve investigator dependence and thereby reproducibility. The completeness of echocardiography will always depend on acoustic windows, which are given in a specific patient. Myocardial perfusion scintigraphy provides the largest database especially on prognosis in coronary artery disease. It has been the <> for the depictions of ischemic and infarcted myocardium. Radiation exposure will always be an issue. Newer hybrid techniques combining nuclear methods with cardiac CT may add arguments, which will be needed for clinical decision-making. Cardiac magnetic resonance has evolved as an important tool in the diagnosis of cardiovascular diseases. It is investigator independent, does not apply any biologically hazardous energy and has the largest potential for tissue characterization due to its high contrast resolution. It therefore is an excellent technique to investigate all the aspects of coronary artery disease. Its availability is increasing, however in order to fully utilize its large potential an optimal collaboration among -specialist (cardiologists, radiologists, physicists) is mandatory. Cardiac CT has evolved as an excellent method for the depiction of the coronary arteries. Due to its high spatial and time resolution it provides high quality luminography of the coronaries and newer technique are also -investigating plaque composition of diseased coronary arteries. Overestimation of coronary artery stenosis in calcified vessels is an inherent problem of the technique and the risk of radiation exposure has to be weighted against the benefit of non-invasively depicting the coronary arteries. It will be the future task of all specialists in this field to define the most efficient and cost-effective way to apply these excellent techniques for the investigation of all the different aspects of patients with coronary artery disease.

Cost-effectiveness of drug-eluting stents in patients at high or low risk of major cardiac events in the Basel Stent KostenEffektivitäts Trial (BASKET): an 18-month analysis.

BACKGROUND: Our aim was to determine whether drug-eluting stents are good value for money in long-term, everyday practice. METHODS: We did an 18-month cost-effectiveness analysis of the Basel Stent KostenEffektivitäts Trial (BASKET), which randomised 826 patients 2:1 to drug-eluting stents (n=545) or to bare-metal stents (281). We used non-parametric bootstrap techniques to determine incremental cost-effectiveness ratios (ICERs) of drug-eluting versus bare-metal stents, to compare low-risk (> or =3.0 mm stents in native vessels; n=558, 68%) and high-risk patients (<3.0 mm stents/bypass graft stenting; n=268, 32%), and to do sensitivity analyses by altering costs and event rates in the whole study sample and in predefined subgroups. Quality-adjusted life-years (QALYs) were assessed by EQ-5D questionnaire (available in 703/826 patients). FINDINGS: Overall costs were higher for patients with drug-eluting stents than in those with bare-metal stents (11,808 euros [SD 400] per patient with drug-eluting stents and 10,450 euros [592] per patient with bare-metal stents, mean difference 1358 euros [717], p<0.0001), due to higher stent costs. We calculated an ICER of 64,732 euros to prevent one major adverse cardiac event, and of 40,467 euros per QALY gained. Stent costs, number of events, and QALYs affected ICERs most, but unrealistic alterations would have been required to achieve acceptable cost-effectiveness. In low-risk patients, the probability of drug-eluting stents achieving an arbitrary ICER of 10,000 euros or less to prevent one major adverse cardiac event was 0.016; by contrast, it was 0.874 in high-risk patients. INTERPRETATION: If used in all patients, drug-eluting stents are not good value for money, even if prices were substantially reduced. Drug-eluting stents are cost effective in patients needing small vessel or bypass graft stenting, but not in those who require large native vessel stenting.

Value and limitations of target-vessel ischemia in predicting late clinical events after drug-eluting stent implantation.

UNLABELLED: Drug-eluting stents reduce clinical events related to restenosis but may be complicated by late stent-thrombosis. Whereas assessment of target-vessel ischemia by myocardial perfusion scintigraphy identifies relevant restenosis noninvasively, it is unknown whether this technique may also predict late clinical events related to late stent-thrombosis and to restenosis after drug-eluting stent implantation. METHODS: All 826 patients treated with stenting between May 2003 and May 2004 were included in the Basel Stent Cost Effectiveness Trial (Basel Stent Kosten-Effektivitäts Trial, or BASKET) and randomized (2:1) to drug-eluting stents or bare metal stents. Myocardial scintigraphy was performed on 476 (64%) of 747 patients without major events after 6 mo. Patients were followed for 1 y for cardiac death, nonfatal myocardial infarction, and target-vessel revascularization due to restenosis or late stent-thrombosis. RESULTS: The rate of target-vessel ischemia in these patients was lower with drug-eluting stents than with bare metal stents (5.4% vs. 10.4%, P = 0.045), similar to the rates of symptom-driven target-vessel revascularization up to 6 mo (4.6% vs. 7.8%, P = 0.08). Ischemia was silent in 68%. During follow-up, patients with target-vessel ischemia had higher event rates than did patients without ischemia (32.4% vs. 6.1%, P < 0.001); however, ischemia did not predict late stent-thrombosis (0/11 cases). CONCLUSION: The rate of clinical restenosis assessed scintigraphically was lower with drug-eluting stents than with bare metal stents and paralleled that of symptom-driven target-vessel revascularization. Target-vessel ischemia independently predicted late clinical events related to restenosis but not to late stent-thrombosis.

Dimethyl fumarate, a small molecule drug for psoriasis, inhibits Nuclear Factor-kappaB and reduces myocardial infarct size in rats.

Persistent Nuclear Factor-kappaB (NF-kappaB) activation is hypothesized to contribute to myocardial injuries following ischemia-reperfusion. Because inhibition or control of NF-kappaB signaling in the heart probably confers cardioprotection, we determined the potency of the NF-kappaB inhibitor dimethyl fumarate (DMF) in cardiovascular cells, and determined whether administration of DMF translates into beneficial effects in an animal model of myocardial infarction. In rat heart endothelial cells (RHEC), we analysed inhibitory effects of DMF on NF-kappaB using shift assay and immunohistofluorescence. In in vivo experiments, male Sprague Dawley rats undergoing left coronary artery occlusion for 45 min received either DMF (10 mg/kg body weight) or vehicle 90 min before ischemia as well as immediately before ischemia. After 120 min of reperfusion, the hearts were stained with phthalocyanine blue dye and triphenyltetrazolium chloride. Additionally, acute hemodynamic and electrophysiologic effects of DMF were determined in dose-response experiments in isolated perfused rat hearts. DMF inhibited TNF-alpha-induced nuclear entry of NF-kappaB in RHEC. In in vivo experiments, myocardial infarct size was significantly smaller in rats that had received DMF (20.7%+/-9.7% in % of risk area; n=17) than in control rats (28.2%+/-6.2%; n=15). Dose-response experiments in isolated perfused rat hearts excluded acute hemodynamic or electrophysiologic effects as mechanisms for the effects of DMF. DMF inhibits nuclear entry of NF-kappaB in RHEC and reduces myocardial infarct size after ischemia and reperfusion in rats in vivo. There was no indication that the beneficial effects of DMF were due to acute hemodynamic or electrophysiologic influences.

Altered Left Ventricular Geometry and Torsional Mechanics in High Altitude-Induced Pulmonary Hypertension: A Three-Dimensional Echocardiographic Study.

BACKGROUND: Changes in left ventricular (LV) torsion have been related to LV geometry in patients with concomitant long-standing myocardial disease or pulmonary hypertension (PH). We evaluated the effect of acute high altitude-induced isolated PH on LV geometry, volumes, systolic function, and torsional mechanics. METHODS: Twenty-three volunteers were prospectively studied at low altitude and after the second (D3) and third night (D4) at high altitude (4,559 m). LV ejection fraction, multidirectional strains and torsion, LV volumes, sphericity, and eccentricity were derived by speckle-tracking on three-dimensional echocardiographic data sets. Pulmonary pressure was estimated from the transtricuspid pressure gradient (TRPG), LV preload from end-diastolic LV volume, and transmitral over mitral annular E velocity (E/e'). RESULTS: At high altitude, oxygen saturation decreased by 15%-20%, heart rate and cardiac index increased by 15%-20%, and TRPG increased from 21 ± 2 to 37 ± 9 mm Hg (P < .01). LV volumes, preload, ejection fraction, multidirectional strains, and sphericity remained unaffected, but diastolic (1.04 ± 0.07 to 1.09 ± 0.09 on D3/D4, P < .05) and systolic (1.00 ± 0.06 to 1.08 ± 0.1 [D3] and 1.06 ± 0.07 [D4], P < .05) eccentricity slightly increased, indicating mild septal flattening. LV torsion decreased from 2.14 ± 0.85 to 1.34 ± 0.68 (P < .05) and 1.65 ± 0.54 (P = .08) degrees/cm on D3/D4, respectively. Changes in torsion showed a weak inverse relationship to changes in systolic (r = -0.369, P = .013) and diastolic (r = -0.329, P = .032) eccentricity but not to changes in TRPG, heart rate or preload. CONCLUSIONS: High-altitude exposure was associated with mild septal flattening of the LV and reduced ventricular torsion at unchanged global LV function and preload, suggesting a relation between LV geometry and torsional mechanics.

Bradykinin is a mediator, but unlikely a trigger, of antiarrhythmic effects of ischemic preconditioning.

OBJECTIVE: Brief reversible ischemic episodes (ischemic preconditioning, IPC) protect the heart against arrhythmias during a subsequent prolonged low-flow ischemia. We have recently shown that this protection involves release of bradykinin, activation of bradykinin B2 receptors followed by opening of sarcolemmal, but not mitochondrial ATP-sensitive K+ channels. The goal of this study was to clarify a trigger and/or mediator role of bradykinin in the antiarrhythmic effects of IPC during low-flow ischemia. METHODS: Isolated perfused rat hearts underwent 60 minutes of low-flow ischemia induced by reducing perfusion pressure followed by 60 minutes of reperfusion. Preconditioning was induced by 2 x 5 minutes episodes of zero-flow ischemia. In yet other groups, preconditioned or non-preconditioned hearts were treated either with bradykinin (10 nmol/L) or with HOE 140 (bradykinin B2 receptor antagonist, 100 nmol/L). RESULTS: IPC reduced the number of ventricular premature beats, as well as the incidence of ventricular tachycardia and of ventricular fibrillation during low-flow ischemia. In addition, this protection was abolished by HOE 140 given during low-flow ischemia. Pharmacological preconditioning using short bradykinin perfusion instead of IPC did not show antiarrhythmic effects. However, bradykinin administered during low-flow ischemia and reperfusion reduced the number of ventricular premature beats and the incidence of ventricular tachycardia and of ventricular fibrillation during low-flow ischemia. CONCLUSION: Bradykinin is a mediator, but unlikely a trigger, of antiarrhythmic effects of IPC during low-flow ischemia.

Effects of percutaneous coronary interventions in silent ischemia after myocardial infarction: the SWISSI II randomized controlled trial.

CONTEXT: The effect of a percutaneous coronary intervention (PCI) on the long-term prognosis of patients with silent ischemia after a myocardial infarction (MI) is not known. OBJECTIVE: To determine whether PCI compared with drug therapy improves long-term outcome of asymptomatic patients with silent ischemia after an MI. DESIGN, SETTING, AND PARTICIPANTS: Randomized, unblinded, controlled trial (Swiss Interventional Study on Silent Ischemia Type II [SWISSI II]) conducted from May 2, 1991, to February 25, 1997, at 3 public hospitals in Switzerland of 201 patients with a recent MI, silent myocardial ischemia verified by stress imaging, and 1- or 2-vessel coronary artery disease. Follow-up ended on May 23, 2006. INTERVENTIONS: Percutaneous coronary intervention aimed at full revascularization (n = 96) or intensive anti-ischemic drug therapy (n = 105). All patients received 100 mg/d of aspirin and a statin. MAIN OUTCOME MEASURES: Survival free of major adverse cardiac events defined as cardiac death, nonfatal MI, and/or symptom-driven revascularization. Secondary measures included exercise-induced ischemia and resting left ventricular ejection fraction during follow-up. RESULTS: During a mean (SD) follow-up of 10.2 (2.6) years, 27 major adverse cardiac events occurred in the PCI group and 67 events occurred in the anti-ischemic drug therapy group (adjusted hazard ratio, 0.33; 95% confidence interval, 0.20-0.55; P<.001), which corresponds to an absolute event reduction of 6.3% per year (95% confidence interval, 3.7%-8.9%; P<.001). Patients in the PCI group had lower rates of ischemia (11.6% vs 28.9% in patients in the drug therapy group at final follow-up; P = .03) despite fewer drugs. Left ventricular ejection fraction remained preserved in PCI patients (mean [SD] of 53.9% [9.9%] at baseline to 55.6% [8.1%] at final follow-up) and decreased significantly (P<.001) in drug therapy patients (mean [SD] of 59.7% [11.8%] at baseline to 48.8% [7.9%] at final follow-up). CONCLUSION: Among patients with recent MI, silent myocardial ischemia verified by stress imaging, and 1- or 2-vessel coronary artery disease, PCI compared with anti-ischemic drug therapy reduced the long-term risk of major cardiac events. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00387231.

Incremental cost-effectiveness of drug-eluting stents compared with a third-generation bare-metal stent in a real-world setting: randomised Basel Stent Kosten Effektivitäts Trial (BASKET).

BACKGROUND: No prospective trial-based data are available for incremental cost-effectiveness of drug-eluting stents (DES) compared with bare-metal stents (BMS) in unselected patients, as treated in everyday practice. METHODS: The Basel stent cost-effectiveness trial (BASKET) included 826 consecutive patients treated with angioplasty and stenting for 1281 de-novo lesions, irrespective of indication for angioplasty. Patients were randomised to one of two DES (Cypher, n=264; Taxus, n=281) or to a cobalt-chromium-based BMS (Vision, n=281) and followed up for 6 months for occurrence of major adverse cardiac events and costs. Analysis was by intention-to-treat. The primary endpoint was cost-effectiveness after 6 months, with effectiveness defined as reduction of major adverse cardiac events. FINDINGS: Cardiac death, myocardial infarction, or target vessel revascularisation occurred in 39 of 544 (7.2%) patients with DES and 34 of 280 (12.1%) with BMS (odds ratio 0.56, 95% CI 0.35-0.91; p=0.02), without significant differences between the two DES. Total costs at 6 months were higher with DES (mean 10,544, SD 6849) than with BMS (9639, 9067; p<0.0001); higher stent costs of DES were not compensated for by lower follow-up costs. Incremental cost-effectiveness ratio of DES compared with BMS to avoid one major event was 18,311, and costs per quality-adjusted life-year gained were more than 50 000. Subgroup analyses showed that DES were more cost-effective for elderly patients in specific high-risk groups. INTERPRETATION: In a real-world setting, use of DES in all patients is less cost effective than in studies with selected patients. Use of these stents could be restricted to patients in high-risk groups.

Early clinical experience with CardioCard - a credit card-sized electronic patient record.

QUESTIONS UNDER STUDY: CardioCard is a CDROM of credit card size containing medical information on cardiac patients. Patient data acquired during hospital stay are stored in PDF format and secured by a password known to patients only. In a consecutive series of patients, we assessed acceptance and utility of this new information medium. METHODS AND RESULTS: A questionnaire was sent to all patients who had received CardioCard over a one-year period. The questionnaire was returned by 392 patients (73%). 44% of patients had the card with them all the time. The majority of patients (73%) considered the CardioCard useful (8% not useful, 19% no statement) and most (78%) would even agree to bear additional costs. Only 5% worried about data security. In contrast, 44% would be concerned of data transmission via internet. During an observation period of 6 (SD 3) months, data were accessed by 27% of patients and 12% of their physicians. The proportion of card users was lower among older patients: < or = 50 years (y), 39%; 51.60 y, 38%; 61.70 y, 26%; >70 y, 16% and particularly among older women: 61.70 y, 9%; >70 y, 5%. Technical problems during data access occurred in 34%, mostly due to incorrect handling. CONCLUSIONS: A majority of patients considered CardioCard as useful and safe. Lack of hardware equipment or insufficient computer knowledge, but not safety issues were the most important limitations. As patients expressed concerns regarding protection of privacy if data were accessible via internet, this would remain a strong limiting factor for online use.

Coronary vasoregulation in patients with various risk factors in response to cold pressor testing: contrasting myocardial blood flow responses to short- and long-term vitamin C administration.

OBJECTIVES: We sought to determine whether abnormal myocardial blood flow (MBF) responses to the cold pressor test (CPT) in patients with various risk factors may involve different mechanisms that could lead to varying responses of short- and long-term administration of antioxidants. BACKGROUND: There is a growing body of evidence that increased vascular production of reactive oxygen species markedly reduces the bioavailability of endothelium-derived nitric oxide, leading to impaired vasodilator function. It is unknown whether increased oxidative stress is the prevalent mechanism underlying endothelial dysfunction in patients with different coronary risk factors. METHODS: Fifty patients with normal coronary angiograms were studied. The MBF responses to CPT was determined by means of positron emission tomography before and after intravenous infusion of 3 g vitamin C or saline (placebo), as well as after 3 months and 2 years of 2 g vitamin C or placebo supplementation daily. RESULTS: In hypertensive patients, the change in MBF (DeltaMBF) was not modified significantly by short-term vitamin C administration challenges (0.20 +/- 0.20 ml/g/min; p = NS) but was significantly increased after three months and two years of treatment with vitamin C versus baseline (0.58 +/- 0.27 and 0.63 +/- 0.17 vs. 0.14 +/- 0.18 ml/g/min; both p < or = 0.001). In smokers, DeltaMBF in response to CPT was significantly increased after short-term vitamin C infusion and long-term vitamin C treatment (0.52 +/- 0.10, 0.54 +/- 0.13, 0.50 +/- 0.07 vs. -0.08 +/- 0.10 ml/g/min; all p < or = 0.001). In hypercholesterolemic patients, no improvement in DeltaMBF during CPT was observed after short- and long-term vitamin C treatment (0.05 +/- 0.14, 0.08 +/- 0.18, 0.02 +/- 0.19 vs. 0.08 +/- 0.16 ml/g/min; p = NS). The CPT-induced DeltaMBF in hypertensive patients and smokers after follow-up was significant as compared with placebo and control subjects (p < or = 0.001). CONCLUSIONS: The present study revealed marked heterogeneous responses in MBF changes to short- and long-term vitamin C treatment in patients with various risk factors, which highlights the quite complex nature underlying abnormal coronary vasomotion.

Long-term outcome of patients with silent versus symptomatic ischemia six months after percutaneous coronary intervention and stenting.

OBJECTIVES: We sought to evaluate the incidence of silent ischemia versus symptomatic ischemia six months after percutaneous coronary intervention (PCI) and its impact on prognosis and to test the utility of myocardial perfusion single-photon emission computed tomography (SPECT), or MPS, for risk stratification in these patients. BACKGROUND: Silent ischemia is frequent after PCI. However, little is known about silent ischemia and long-term outcome after PCI and stenting. METHODS: In 356 consecutive patients with successful PCI and stenting and follow-up MPS after six months, long-term follow-up (4.1 +/- 0.3 years) was performed. The MPS images were interpreted by defining summed stress, rest, and difference scores (summed difference score [SDS] = extent of ischemia) and related to symptoms and outcome. Critical events included cardiac death, myocardial infarction, and target vessel revascularization. RESULTS: Eighty-one patients (23%) had evidence of target vessel ischemia, which was silent in 62%. The only independent predictor of silent ischemia was SDS (odds ratio 0.64, p = 0.001). During follow-up, 67 critical events occurred. For patients with an SDS of 0, 1-4, and >4, the critical event rates were 17%, 29%, and 69%, respectively. Similarly, patients without ischemia, silent ischemia, and symptomatic ischemia had 17%, 32%, and 52% of critical events, respectively. Diabetes (relative risk 1.98, p = 0.03) and SDS (relative risk 1.2, p < 0.001) were independent predictors of critical events. The MPS image added incremental information for the prediction of critical events. CONCLUSIONS: Six months after PCI and stenting, 23% of patients had target vessel ischemia, which was silent in 62%. Silent ischemia predicted a worse outcome than did no ischemia and tended to have a better outcome than symptomatic ischemia. This was closely related to the extent of ischemia. The SDS added incremental value to pre-scan findings with respect to diagnosis and prognosis, indicating the utility of MPS for risk stratification after PCI and stenting.

Influence of revascularization on long-term outcome in patients > or =75 years of age with diabetes mellitus and angina pectoris.

Little is known about the effect of revascularization in patients > or =75 years of age with symptomatic coronary artery disease (CAD) and diabetes mellitus (DM) for whom periprocedural risk and overall mortality are increased. Therefore, we examined the 301 patients of the Trial of Invasive versus Medical therapy in the Elderly with symptomatic CAD (TIME) with special regard to diabetic status. Patients were randomized to an invasive versus optimized medical strategy. The median follow-up was 4.1 years (range 0.1 to 6.9). Patients with DM (n = 69) had a greater incidence of hypertension (73% vs 58%, p = 0.03), > or =2 risk factors (93% vs 46%, p <0.01), previous heart failure (22% vs 12%, p = 0.04), and previous myocardial infarction (59% vs 43%, p = 0.02), and a lower left ventricular ejection fraction (48% vs 54%, p = 0.02) than did patients without DM. Mortality was greater in patients with DM than in those without DM (41% vs 25%, p = 0.01; adjusted hazard ratio 1.86, p = 0.01). Revascularization improved the overall survival rate from 61% (no revascularization) to 79% (p <0.01; adjusted hazard ratio 1.68, p = 0.03), an effect similarly observed in patients with and without DM. The event-free survival rate was 11% in nonrevascularized patients with DM compared with 40% in nonrevascularized patients without DM and 41% and 53% in revascularized patients with and without DM, respectively (p <0.01). Angina severity and antianginal drug use were similar for patients with and without DM, but those with DM performed worse in daily activities and physical functioning. In conclusion, elderly diabetic patients with chronic angina have a worse outcome than those with DM but benefit similarly from revascularization regarding symptom relief and long-term outcome. However, physical functioning related to daily activities is reduced in those with DM and may need special attention.

Prognostic value of abnormal vasoreactivity of epicardial coronary arteries to sympathetic stimulation in patients with normal coronary angiograms.

OBJECTIVE: We aimed to evaluate prospectively whether patients with normal coronary angiogram but abnormal epicardial vasoreactivity to cold pressor test (CPT) are at increased risk for cardiovascular events. METHODS AND RESULTS: Vasoreactivity in response to CPT and dilation of epicardial arteries to intracoronary application of nitroglycerin were assessed quantitatively (percent change of luminal area, DeltaLA%) in 130 patients with normal coronary angiograms. Cardiovascular events (cardiovascular death, acute coronary syndrome, myocardial infarction, percutaneous transluminal coronary angioplasty, coronary bypass grafting, ischemic stroke, or peripheral revascularization) were assessed as clinical outcome parameters over a mean follow-up period of 45+/-9 months. Based on their vascular responses to CPT, patients were assigned into the following 3 groups: group 1, patients with normal vasodilator response (DeltaLA >0%; n=37); group 2, patients with moderate vasoconstrictor response (DeltaLA between 0% and -15%; n=42); and group 3, patients with severe vasoconstrictor response (DeltaLA < or =-15%; n=51). Although patients from groups 2 and 3 had significantly increased vasoconstrictor response to CPT (group 2, DeltaLA -6+/-3% and group 3, DeltaLA -24+/-6% versus group 1, DeltaLA 11+/-9%; P< or =0.0001), they showed normal endothelial-independent epicardial vasodilation to intracoronary application of nitroglycerin similar to patients from group 1 (DeltaLA 39+/-16% and 34+/-14% versus 41+/-14%; P=NS, respectively). During follow-up, none of the patients from group 1 developed cardiac events. However, 7 cardiovascular events occurred in group 2 and 30 occurred in group 3 in 4 and 22 patients, respectively (P< or =0.0001, univariate by log-rank test). After adjustment for known risk factors for coronary artery disease, impaired epicardial coronary vasoreactivity to CPT remained significantly associated with the risk of developing cardiovascular events (P=0.040, multivariate by Cox regression model). CONCLUSIONS: In patients with normal coronary angiogram, abnormal vasoreactivity of epicardial coronary arteries in response to sympathetic stimulation is associated with the risk of developing cardiovascular events.

Echocardiographic quantification of atherosclerosis leads to cost-effective treatment with statins.

OBJECTIVE: Use of statins in prevention of atherosclerosis is effective but expensive. Patient selection gains wider public attention as medication costs in the US and Europe augment by 8% to 10% per year. We examined different clinical risk stratification strategies, particularly focusing on echocardiographic atherosclerosis quantification, for their impact on event reduction and cost-effectiveness in statin treatment. METHODS AND RESULTS: In a prospective, consecutive cohort of 336 patients referred to non-invasive cardiac examination, risk stratification was done by various combinations of risk factors and noninvasive atherosclerosis quantification. Atherosclerotic burden was determined through measuring "aortic elastance" by transthoracic echocardiogram, a validated non-invasive method. Cardiovascular events were recorded at a mean follow-up of one year. Echocardiographically determined atherosclerosis severity and event history, especially in combination, yielded the best selection strategies for statin treatment over a broad range of predetermined funding or required event reductions, surpassing conventional cardiovascular risk factors. From 26.8 statin-preventable events/1000 patients/year (assuming all patients treated), the best selection strategies could avoid: 24 with 66% of the cost for statin treatment (atherosclerosis and age criteria), 20.1 with <50% of the budget, 12.2 with <30% of the budget or 9.6 with <15% of the budget (using combinations of atherosclerosis and prior events), while conventional strategies without echo quantification of atherosclerosis were inferior. CONCLUSION: Non-invasive echocardiographic quantification of atherosclerosis improves efficiency and cost-effectiveness in statin treatment.