Ginés Sanz

Comparison of Low-Molecular-Weight Heparin With Unfractionated Heparin Acutely and With Placebo for 6 Weeks in the Management of Unstable Coronary Artery Disease Fragmin in Unstable Coronary Artery Disease Study (FRIC)

BACKGROUND Low-molecular-weight heparin has a number of pharmacological and pharmacokinetic advantages over unfractionated heparin that make it potentially suitable, when used in combination with aspirin, for the treatment of unstable coronary artery disease. METHOD AND RESULTS Patients with unstable angina or non-Q-wave myocardial infarction (1482) were included in the study, which had two phases. In an open, acute phase (days 1 to 6), patients were assigned either twice-daily weight-adjusted subcutaneous injections of dalteparin (120 i.u./kg) or dose-adjusted intravenous infusion of unfractionated heparin. In the double-blind, prolonged treatment phase (days 6 to 45), patients received subcutaneously either dalteparin (7500 i.u. once daily) or placebo. During the first 6 days, the rate of death, myocardial infarction, or recurrence of angina was 7.6% in the unfractionated heparin-treated patients and 9.3% in the dalteparin-treated patients (relative risk, 1.18; 95% confidence interval [CI], 0.84 to 1.66). The corresponding rates in the two treatment groups for the composite end point of death or myocardial infarction were 3.6% and 3.9%, respectively (relative risk, 1.07; 95% CI, 0.63 to 1.80). Revascularization procedures were undertaken in 5.3% and 4.8% of patients in unfractionated heparin and dalteparin groups, respectively (relative risk, 0.88; 95% CI, 0.57 to 1.35). Between days 6 and 45, the rate of death, myocardial infarction, or recurrence of angina was 12.3% in both the placebo and dalteparin groups (relative risk, 1.01; 95% CI, 0.74 to 1.38). The corresponding rates for death or myocardial infarction were 4.7% and 4.3% (relative risk, 0.92; 95% CI, 0.54 to 1.57). Revascularization procedures were undertaken in 14.2% and 14.3% of patients in the placebo and dalteparin groups, respectively. CONCLUSIONS Our results add to previous evidence suggesting that the low-molecular-weight heparin dalteparin administered by twice-daily subcutaneous injection may be an alternative to unfractionated heparin in the acute treatment of unstable angina or non-Q-wave myocardial infarction. Prolonged treatment with dalteparin at a lower once-daily dose in our study did not confer any additional benefit over aspirin (75 to 165 mg) alone.

Effect of Early Metoprolol on Infarct Size in ST-Segment–Elevation Myocardial Infarction Patients Undergoing Primary Percutaneous Coronary Intervention The Effect of Metoprolol in Cardioprotection During an Acute Myocardial Infarction (METOCARD-CNIC) Trial

Background —The effect of β-blockers on infarct size when used in conjunction with primary percutaneous coronary intervention (PCI) is unknown. We hypothesize that metoprolol reduces infarct size when administered early (intravenously [i.v.] before reperfusion). Methods and Results —Patients with Killip-class ≤II anterior ST-segment elevation myocardial infarction (STEMI) undergoing PCI within 6 hours of symptoms onset were randomized to receive i.v. metoprolol (n=131) or not (control, n=139) pre-reperfusion. All patients without contraindications received oral metoprolol within 24 hours. The pre-defined primary endpoint was infarct size on magnetic resonance imaging (MRI) performed 5-7 days after STEMI. MRI was performed in 220 patients (81%). Mean (±SD) infarct size by MRI was smaller after i.v. metoprolol compared to control (25.6±15.3 vs. 32.0±22.2 grams; adjusted difference, -6.52; 95% confidence interval [CI], -11.39 to -1.78; P=0.012). In patients with pre-PCI TIMI flow grade 0/1, the adjusted treatment difference in infarct size was -8.02; 95% CI, -13.01 to -3.02; P=0.0029. Infarct size estimated by peak and area under the curve creatine-kinase release was measured in all study population and was significantly reduced by i.v. metoprolol. Left ventricular ejection fraction was higher in the i.v. metoprolol group (adjusted difference 2.67%; 95% CI, 0.09% to 5.21%; P=0.045). The composite of death, malignant ventricular arrhythmia, cardiogenic shock, atrioventricular block and reinfarction at 24 hours in the i.v. metoprolol and control groups respectively was 7.1% vs. 12.3%, p=0.21. Conclusions —In patients with anterior Killip-class ≤II STEMI undergoing primary PCI, early i.v. metoprolol before reperfusion reduced infarct size and increased LVEF with no excess of adverse events during the first 24 hours after STEMI. Clinical Trial Registration Information —ClinicalTrials.gov. Identifier: [NCT01311700][1] & EUDRACT Number 2010-019939-35. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01311700&atom=%2Fcirculationaha%2Fearly%2F2013%2F09%2F03%2FCIRCULATIONAHA.113.003653.atomBackground— The effect of &bgr;-blockers on infarct size when used in conjunction with primary percutaneous coronary intervention is unknown. We hypothesize that metoprolol reduces infarct size when administered early (intravenously before reperfusion). Methods and Results— Patients with Killip class II or less anterior ST-segment–elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention within 6 hours of symptoms onset were randomized to receive intravenous metoprolol (n=131) or not (control, n=139) before reperfusion. All patients without contraindications received oral metoprolol within 24 hours. The predefined primary end point was infarct size on magnetic resonance imaging performed 5 to 7 days after STEMI. Magnetic resonance imaging was performed in 220 patients (81%). Mean±SD infarct size by magnetic resonance imaging was smaller after intravenous metoprolol compared with control (25.6±15.3 versus 32.0±22.2 g; adjusted difference, −6.52; 95% confidence interval, −11.39 to −1.78; P=0.012). In patients with pre–percutaneous coronary intervention Thrombolysis in Myocardial Infarction grade 0 to 1 flow, the adjusted treatment difference in infarct size was −8.13 (95% confidence interval, −13.10 to −3.16; P=0.0024). Infarct size estimated by peak and area under the curve creatine kinase release was measured in all study populations and was significantly reduced by intravenous metoprolol. Left ventricular ejection fraction was higher in the intravenous metoprolol group (adjusted difference, 2.67%; 95% confidence interval, 0.09–5.21; P=0.045). The composite of death, malignant ventricular arrhythmia, cardiogenic shock, atrioventricular block, and reinfarction at 24 hours in the intravenous metoprolol and control groups was 7.1% and 12.3%, respectively (P=0.21). Conclusions— In patients with anterior Killip class II or less ST-segment–elevation myocardial infarction undergoing primary percutaneous coronary intervention, early intravenous metoprolol before reperfusion reduced infarct size and increased left ventricular ejection fraction with no excess of adverse events during the first 24 hours after STEMI. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01311700. EUDRACT number: 2010-019939-35.

Prognostic value of serum cytokines in patients with congestive heart failure

BACKGROUND Increased levels of circulating cytokines have been previously reported in patients with congestive heart failure; however, whether they have prognostic implications is still unknown. The aim of this study was to assess the prognostic implications of elevated serum cytokines in patients with heart failure and to identify the predictors of cytokine activation. METHODS AND RESULTS We assessed neurohormonal determinations, circulating cytokines, ejection fraction (EF) and end-diastolic and end-systolic left ventricular lengths in 87 patients (aged 57 +/- 9 years) with left ventricular dysfunction (EF 24% +/- 6%). In 48 patients, we also assessed cytokine receptors. During follow-up (mean, 14 +/- 9 months), 8 patients died and 12 had new heart failure episodes that required hospital admission, 5 of whom underwent heart transplantation. The univariate predictors of these events were serum interleukin-6 (IL-6) (p = 0.00001), New York Heart Association (NYHA) functional class (p = 0.0004), tumor necrosis factor-soluble receptor I (p = 0. 001), atrial natriuretic peptide (p = 0.002), tumor necrosis factor-soluble receptor II (p = 0.004), angiotensin II (p = 0.006), serum interleukin-1 beta (p = 0.01), and plasma renin activity (p = 0.02). Increased serum interleukin-6 (>10 pg/ml) was a significant predictor of death or new heart failure episodes according to the Kaplan-Meier survival method by log-rank test (p = 0.004). By Cox regression analysis, serum IL-6 (p = 0.0005) and the NYHA functional class (p = 0.005) were identified as independent predictors of prognosis. CONCLUSIONS In patients with congestive heart failure, increased serum IL-6 was identified as a powerful independent predictor of the combined end point: death, new heart failure episodes, and need for heart transplantation.

Myocardial infarction with normal coronary arteries: A prospective clinical-angiographic study

The association of myocardial infarction with normal coronary arteries was analyzed prospectively. A series of 259 consecutive men aged 60 years or less underwent selective coronary angiography 30 days after a definite infarct. Coronary arterial lesions were documented in 251 patients, normal coronary arteries in the remaining 8. The latter patients had a significantly lower (p less than 0.001) mean age than the former; no patient older than 50 years had patent coronary arteries, whereas 5 of the 11 patients under age 35 had normal arteries. The prevalence of risk factors was similar in both groups of patients. Although there were no group differences in infarct size or location, patients with normal coronary arteries had a higher ejection fraction (p less than 0.01) and a lower left ventricular end-diastolic pressure (p less than 0.05). A previous history of angina or infarction and the occurrence of new coronary events were confined to patients with coronary arterial lesions. The clinical course of patients presenting with normal angiograms was uneventful. Transient coronary occlusion, the most likely mechanism of infarction in this group of patients, could not be ascribed to either spasm or platelet hyperactivity.

Short-Term Effects of Transdermal Estrogen Replacement Therapy on Coronary Vascular Reactivity in Postmenopausal Women With Angina Pectoris and Normal Results on Coronary Angiograms

OBJECTIVES This study sought to analyze the effect of short-term transdermal estradiol treatment on in vivo coronary endothelial function in postmenopausal women with angina and normal results on coronary arteriograms. BACKGROUND The incidence of coronary heart disease increases in women after menopause. Estrogen replacement therapy has been associated with a global reduction in cardiovascular disease incidence and mortality. In addition, coronary endothelial dysfunction has been demonstrated in a group of postmenopausal women. It has been shown that intravenous or intracoronary estrogens improve endothelial function in postmenopausal women with coronary atherosclerosis. However, the efficacy of this treatment is unknown in patients with angina and normal coronary arteries. METHODS Endothelium-dependent coronary reactivity was analyzed in 15 postmenopausal women with angina and normal coronary arteries at baseline and after 24 h of estradiol transdermal administration (100 microg). RESULTS Estradiol concentration increased from 22 +/- 8 pg/ml (mean +/- SEM) at baseline to 76 +/- 13 pg/ml (p < 0.01) at 24 h. At baseline, acetylcholine induced vasoconstriction, with a mean diameter reduction of -23 +/- 6% (p = 0.002). After estrogen treatment, there was no vasoconstriction with acetylcholine, with a mean diameter change of 0 +/- 4%, significantly different from the pretreatment diameter reduction observed (p = 0.003). Similarly, estimated coronary blood flow significantly increased in response to acetylcholine after estrogen treatment, with a mean change of 50 +/- 30% compared with 5 +/- 24% before estradiol administration (p = 0.04). CONCLUSIONS Early after transdermal estrogen administration, endothelium-dependent coronary vasomotion is improved in postmenopausal women with angina and normal coronary arteries.

Serum interleukin-6 in congestive heart failure secondary to idiopathic dilated cardiomyopathy

Increased serum interleukin-6 (IL-6) was associated with a higher incidence of New York Heart Association functional classes III to IV and worse left ventricular function during follow-up. Patients with elevated serum IL-6 had poor prognosis. These results reinforce the concept that increased serum IL-6 may also play an important role in disease progression.

Angiographic findings 1 month after myocardial infarction: a prospective study of 259 survivors.

Coronary anatomy as it relates to left ventricular function was assessed prospectively in patients who survived acute myocardial infarction. The study population included 259 consecutive male patients age 60 years or younger who underwent catheterization 30 days after the acute event. Coronary artery obstructive lesions (> 50% reduction in luminal diameter) were found in 241 patients (93%), 118 (45%) of whom had total and 76 (29%) subtotal (> 90%) stenosis) occlusion of at least one coronary artery. Normal coronary vessels were seen in eight patients (3%) and nonobstructive lesions in 10 (4%). One-, two- and threevessel disease were present in 89, 86 and 66 patients, respectively. Patients with normal coronary arteries or nonobstructive lesions had higher ejection fractions than those with obstructive lesions in one, two or three vessels (p < 0.05). Ejection fraction was lower (p < 0.001) and the percentage of akinetic segments higher (p < 0.001) in patients with total or subtotal lesions and no collaterals. Adequate collaterals, seen in 29 patients (11%), significantly improved regional wall motion (p < 0.05) and decreased the percentage of akinetic segments (p < 0.001). Thus, in a substantial number of patients (32% in our series), the infarcted area is spontaneously reperfused by collaterals or through the involved artery. Both mechanisms ameliorate wall motion in corresponding areas.

Prevalence, Vascular Distribution, and Multiterritorial Extent of Subclinical Atherosclerosis in a Middle-Aged Cohort The PESA (Progression of Early Subclinical Atherosclerosis) Study

Background— Data are limited on the presence, distribution, and extent of subclinical atherosclerosis in middle-aged populations. Methods and Results— The PESA (Progression of Early Subclinical Atherosclerosis) study prospectively enrolled 4184 asymptomatic participants 40 to 54 years of age (mean age, 45.8 years; 63% male) to evaluate the systemic extent of atherosclerosis in the carotid, abdominal aortic, and iliofemoral territories by 2-/3-dimensional ultrasound and coronary artery calcification by computed tomography. The extent of subclinical atherosclerosis, defined as presence of plaque or coronary artery calcification ≥1, was classified as focal (1 site affected), intermediate (2–3 sites), or generalized (4–6 sites) after exploration of each vascular site (right/left carotids, aorta, right/left iliofemorals, and coronary arteries). Subclinical atherosclerosis was present in 63% of participants (71% of men, 48% of women). Intermediate and generalized atherosclerosis was identified in 41%. Plaques were most common in the iliofemorals (44%), followed by the carotids (31%) and aorta (25%), whereas coronary artery calcification was present in 18%. Among participants with low Framingham Heart Study (FHS) 10-year risk, subclinical disease was detected in 58%, with intermediate or generalized disease in 36%. When longer-term risk was assessed (30-year FHS), 83% of participants at high risk had atherosclerosis, with 66% classified as intermediate or generalized. Conclusions— Subclinical atherosclerosis was highly prevalent in this middle-aged cohort, with nearly half of the participants classified as having intermediate or generalized disease. Most participants at high FHS risk had subclinical disease; however, extensive atherosclerosis was also present in a substantial number of low-risk individuals, suggesting added value of imaging for diagnosis and prevention. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01410318.

Clinical profile of Trypanosoma cruzi infection in a non-endemic setting: Immigration and Chagas disease in Barcelona (Spain)

BACKGROUND Chagas disease is no longer limited to Latin America and is becoming frequent in industrialised countries in Europe and United States. METHODS A descriptive study of Latin American immigrants in Barcelona attending two centres for imported diseases during a period of 3 years. The main outcome was the identification of Trypanosoma cruzi-infected individuals in a non-endemic country and the characterization of their clinical and epidemiological features. RESULTS A total of 489 Latin American patients participated in the study. Forty-one percent were infected by T. cruzi, and the most frequent country of origin was Bolivia. All T. cruzi infected patients were in chronic stages of infection. 19% of cases had cardiac disorders and 9% had digestive disorders. CONCLUSIONS A high percentage of participants in this study were infected by T. cruzi and various factors were found to be associated to the infection. It is important to improve clinical and epidemiological knowledge of T. cruzi infection in non-endemic countries and to develop appropriate screening and treatment protocols in these settings.

Prevention of early aortocoronary bypass occlusion by low-dose aspirin and dipyridamole. Grupo Español para el Seguimiento del Injerto Coronario (GESIC)

To analyze the efficacy of low-dose aspirin in preventing early aortocoronary vein graft occlusion, 1,112 consecutive patients were enrolled in a multicenter, randomized, double-blind, placebo-controlled trial comparing 50 mg t.i.d. aspirin, 50 mg aspirin plus 75 mg t.i.d. dipyridamole, and placebo. All patients received 100 mg q.i.d. dipyridamole for 48 hours before surgery, and assigned treatment was started 7 hours after surgery. Vein graft angiography was performed in 927 patients (83%) within 28 days of surgery (mean, 10 days). Aspirin plus dipyridamole significantly (p = 0.017) reduced the occlusion rate of distal anastomoses from 18% (placebo) to 12.9%. Occlusion rate in the aspirin group was 14%, which approached statistical significance (p = 0.058). Furthermore, only aspirin plus dipyridamole reduced (p = 0.01) the number of patients with occluded grafts (placebo, 33%; aspirin, 27.1%; aspirin plus dipyridamole, 24.3%). Mediastinal drainage was slightly higher (p = 0.04) in the aspirin plus dipyridamole group (713 +/- 456 ml) than in the other two groups (placebo, 670 +/- 437 ml; aspirin, 629 +/- 337 ml), but hospital mortality (average, 4.6%) and early reoperation (average, 3.9%) rates were similar among the three groups. Thus, low-dose aspirin plus dipyridamole safely improves early saphenous vein aortocoronary graft patency; this effect is an added benefit to a preoperative regimen of dipyridamole.