Ana García-Álvarez

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.

Right ventriculo-arterial coupling in pulmonary hypertension: a magnetic resonance study

Objective To quantify right ventriculo-arterial coupling in pulmonary hypertension by combining standard right heart catheterisation (RHC) and cardiac magnetic resonance (CMR) and to estimate it non-invasively with CMR alone. Design Cross-sectional analysis in a retrospective cohort of consecutive patients. Setting Tertiary care centre. Patients 139 adults referred for pulmonary hypertension evaluation. Interventions CMR and RHC within 2 days (n=151 test pairs). Main outcome measures Right ventriculo-arterial coupling was quantified as the ratio of pulmonary artery (PA) effective elastance (Ea, index of arterial load) to right ventricular maximal end-systolic elastance (Emax, index of contractility). Right ventricular end-systolic volume (ESV) and stroke volume (SV) were obtained from CMR and adjusted to body surface area. RHC provided mean PA pressure (mPAP) as a surrogate of right ventricular end-systolic pressure, pulmonary capillary wedge pressure (PCWP) and pulmonary vascular resistance index (PVRI). Ea was calculated as (mPAP − PCWP)/SV and Emax as mPAP/ESV. Results Ea increased linearly with advancing severity as defined by PVRI quartiles (0.19, 0.50, 0.93 and 1.63 mm Hg/ml/m2, respectively; p<0.001 for trend) whereas Emax increased initially and subsequently tended to decrease (0.52, 0.67, 0.54 and 0.56 mm Hg/ml/m2; p=0.7). Ea/Emax was maintained early but increased markedly with severe hypertension (0.35, 0.72, 1.76 and 2.85; p<0.001), indicating uncoupling. Ea/Emax approximated non-invasively with CMR as ESV/SV was 0.75, 1.17, 2.28 and 3.51, respectively (p<0.001). Conclusions Right ventriculo-arterial coupling in pulmonary hypertension can be studied with standard RHC and CMR. Arterial load increases with disease severity whereas contractility cannot progress in parallel, leading to severe uncoupling.

Myocardial Edema After Ischemia/Reperfusion Is Not Stable and Follows a Bimodal Pattern: Imaging and Histological Tissue Characterization

BACKGROUND It is widely accepted that edema occurs early in the ischemic zone and persists in stable form for at least 1 week after myocardial ischemia/reperfusion. However, there are no longitudinal studies covering from very early (minutes) to late (1 week) reperfusion stages confirming this phenomenon. OBJECTIVES This study sought to perform a comprehensive longitudinal imaging and histological characterization of the edematous reaction after experimental myocardial ischemia/reperfusion. METHODS The study population consisted of 25 instrumented Large-White pigs (30 kg to 40 kg). Closed-chest 40-min ischemia/reperfusion was performed in 20 pigs, which were sacrificed at 120 min (n = 5), 24 h (n = 5), 4 days (n = 5), and 7 days (n = 5) after reperfusion and processed for histological quantification of myocardial water content. Cardiac magnetic resonance (CMR) scans with T2-weighted short-tau inversion recovery and T2-mapping sequences were performed at every follow-up stage until sacrifice. Five additional pigs sacrificed after baseline CMR served as controls. RESULTS In all pigs, reperfusion was associated with a significant increase in T2 relaxation times in the ischemic region. On 24-h CMR, ischemic myocardium T2 times returned to normal values (similar to those seen pre-infarction). Thereafter, ischemic myocardium-T2 times in CMR performed on days 4 and 7 after reperfusion progressively and systematically increased. On day 7 CMR, T2 relaxation times were as high as those observed at reperfusion. Myocardial water content analysis in the ischemic region showed a parallel bimodal pattern: 2 high water content peaks at reperfusion and at day 7, and a significant decrease at 24 h. CONCLUSIONS Contrary to the accepted view, myocardial edema during the first week after ischemia/reperfusion follows a bimodal pattern. The initial wave appears abruptly upon reperfusion and dissipates at 24 h. Conversely, the deferred wave of edema appears progressively days after ischemia/reperfusion and is maximal around day 7 after reperfusion.

Long-term benefit of early pre-reperfusion metoprolol administration in patients with acute myocardial infarction: results from the METOCARD-CNIC trial (Effect of Metoprolol in Cardioprotection During an Acute Myocardial Infarction)

OBJECTIVES The goal of this trial was to study the long-term effects of intravenous (IV) metoprolol administration before reperfusion on left ventricular (LV) function and clinical events. BACKGROUND Early IV metoprolol during ST-segment elevation myocardial infarction (STEMI) has been shown to reduce infarct size when used in conjunction with primary percutaneous coronary intervention (pPCI). METHODS The METOCARD-CNIC (Effect of Metoprolol in Cardioprotection During an Acute Myocardial Infarction) trial recruited 270 patients with Killip class ≤II anterior STEMI presenting early after symptom onset (<6 h) and randomized them to pre-reperfusion IV metoprolol or control group. Long-term magnetic resonance imaging (MRI) was performed on 202 patients (101 per group) 6 months after STEMI. Patients had a minimal 12-month clinical follow-up. RESULTS Left ventricular ejection fraction (LVEF) at the 6 months MRI was higher after IV metoprolol (48.7 ± 9.9% vs. 45.0 ± 11.7% in control subjects; adjusted treatment effect 3.49%; 95% confidence interval [CI]: 0.44% to 6.55%; p = 0.025). The occurrence of severely depressed LVEF (≤35%) at 6 months was significantly lower in patients treated with IV metoprolol (11% vs. 27%, p = 0.006). The proportion of patients fulfilling Class I indications for an implantable cardioverter-defibrillator (ICD) was significantly lower in the IV metoprolol group (7% vs. 20%, p = 0.012). At a median follow-up of 2 years, occurrence of the pre-specified composite of death, heart failure admission, reinfarction, and malignant arrhythmias was 10.8% in the IV metoprolol group versus 18.3% in the control group, adjusted hazard ratio (HR): 0.55; 95% CI: 0.26 to 1.04; p = 0.065. Heart failure admission was significantly lower in the IV metoprolol group (HR: 0.32; 95% CI: 0.015 to 0.95; p = 0.046). CONCLUSIONS In patients with anterior Killip class ≤II STEMI undergoing pPCI, early IV metoprolol before reperfusion resulted in higher long-term LVEF, reduced incidence of severe LV systolic dysfunction and ICD indications, and fewer heart failure admissions. (Effect of METOprolol in CARDioproteCtioN During an Acute Myocardial InfarCtion. The METOCARD-CNIC Trial; NCT01311700).

Long term benefit of early pre-reperfusion metoprolol administration in patients with acute myocardial infarction: results from the METOCARD-CNIC trial.

OBJECTIVES The goal of this trial was to study the long-term effects of intravenous (IV) metoprolol administration before reperfusion on left ventricular (LV) function and clinical events. BACKGROUND Early IV metoprolol during ST-segment elevation myocardial infarction (STEMI) has been shown to reduce infarct size when used in conjunction with primary percutaneous coronary intervention (pPCI). METHODS The METOCARD-CNIC (Effect of Metoprolol in Cardioprotection During an Acute Myocardial Infarction) trial recruited 270 patients with Killip class ≤II anterior STEMI presenting early after symptom onset (<6 h) and randomized them to pre-reperfusion IV metoprolol or control group. Long-term magnetic resonance imaging (MRI) was performed on 202 patients (101 per group) 6 months after STEMI. Patients had a minimal 12-month clinical follow-up. RESULTS Left ventricular ejection fraction (LVEF) at the 6 months MRI was higher after IV metoprolol (48.7 ± 9.9% vs. 45.0 ± 11.7% in control subjects; adjusted treatment effect 3.49%; 95% confidence interval [CI]: 0.44% to 6.55%; p = 0.025). The occurrence of severely depressed LVEF (≤35%) at 6 months was significantly lower in patients treated with IV metoprolol (11% vs. 27%, p = 0.006). The proportion of patients fulfilling Class I indications for an implantable cardioverter-defibrillator (ICD) was significantly lower in the IV metoprolol group (7% vs. 20%, p = 0.012). At a median follow-up of 2 years, occurrence of the pre-specified composite of death, heart failure admission, reinfarction, and malignant arrhythmias was 10.8% in the IV metoprolol group versus 18.3% in the control group, adjusted hazard ratio (HR): 0.55; 95% CI: 0.26 to 1.04; p = 0.065. Heart failure admission was significantly lower in the IV metoprolol group (HR: 0.32; 95% CI: 0.015 to 0.95; p = 0.046). CONCLUSIONS In patients with anterior Killip class ≤II STEMI undergoing pPCI, early IV metoprolol before reperfusion resulted in higher long-term LVEF, reduced incidence of severe LV systolic dysfunction and ICD indications, and fewer heart failure admissions. (Effect of METOprolol in CARDioproteCtioN During an Acute Myocardial InfarCtion. The METOCARD-CNIC Trial; NCT01311700).

RV dysfunction in pulmonary hypertension is independently related to pulmonary artery stiffness.

OBJECTIVES This study investigated whether right ventricular (RV) adaptation to chronic pressure overload is associated with pulmonary artery (PA) stiffness beyond the degree of severity of pulmonary hypertension (PH). BACKGROUND Increased PA stiffness has been associated with reduced survival in PH. The mechanisms for this association remain unclear. METHODS Right heart catheterization and cardiac magnetic resonance were performed within 1 week in 124 patients with known or suspected chronic PH. Pulmonary vascular resistance index (PVRI) and PA pressures were quantified from right heart catheterization. Cardiac magnetic resonance included standard biventricular cine sequences and main PA flow quantification with phase-contrast imaging. Indexes of PA stiffness (elasticity, distensibility, capacitance, stiffness index beta, and pulse pressure) were quantified combining right heart catheterization and cardiac magnetic resonance data. RV performance and adaptation were measured by RV ejection fraction, right ventricular mass index (RVMI), RV end-systolic volume index, and right ventricular stroke work index (RVSWI). RESULTS All indexes of PA stiffness were significantly correlated with measures of RV performance (Spearman rho coefficients ranging from -0.20 to 0.61, p < 0.05). Using multivariate regression analysis, PA elasticity, distensibility, and index beta were independently associated with all measures of RV performance after adjusting PVRI (p ≤ 0.024). PA capacitance was independently associated with RV ejection fraction, RVMI, and RVSWI (p < 0.05), whereas PA pulse pressure was associated with RVMI and RVSWI (p ≤ 0.027). Compared with PVRI, PA elasticity, distensibility, capacitance, and index beta explained 15% to 68% of the variability in RV ejection fraction, RVMI, and RV end-systolic volume index. Relative contributions of PA stiffness for RVSWI were 1.2× to 18.0× higher than those of PVRI. CONCLUSIONS PA stiffness is independently associated with the degree of RV dysfunction, dilation, and hypertrophy in PH. RV adaptation to chronic pressure overload is related not only to the levels of vascular resistance (steady afterload), but also to PA stiffness (pulsatile load).

Chagas Cardiomiopathy: The Potential of Diastolic Dysfunction and Brain Natriuretic Peptide in the Early Identification of Cardiac Damage

Introduction Chagas disease remains a major cause of mortality in several countries of Latin America and has become a potential public health problem in non-endemic countries as a result of migration flows. Cardiac involvement represents the main cause of mortality, but its diagnosis is still based on nonspecific criteria with poor sensitivity. Early identification of patients with cardiac involvement is desirable, since early treatment may improve prognosis. This study aimed to assess the role of diastolic dysfunction, abnormal myocardial strain and elevated brain natriuretic peptide (BNP) in the early identification of cardiac involvement in Chagas disease. Methodology/Principal Findings Fifty-four patients divided into 3 groups—group 1 (undetermined form: positive serology without ECG or 2D-echocardiographic abnormalities; N = 32), group 2 (typical ECG abnormalities of Chagas disease but normal 2D-echocardiography; N = 14), and group 3 (regional wall motion abnormalities, left ventricular [LV] end-diastolic diameter >55 mm or LV ejection fraction <50% on echocardiography; N = 8)—and 44 control subjects were studied. Patients with significant non-cardiac diseases, other heart diseases and previous treatment with benznidazol were excluded. The median age was 37 (20–58) years; 40% were men. BNP levels, longitudinal and radial myocardial strain and LV diastolic dysfunction increased progressively from group 1 to 3 (p for trend <0.01). Abnormal BNP levels (>37 pg/ml) were noted in 0%, 13%, 29% and 63% in controls and groups 1 to 3, respectively. Half of patients in the undetermined form had impaired relaxation patterns, whereas half of patients with ECG abnormalities suggestive of Chagas cardiomyopathy had normal diastolic function. In group 1, BNP levels were statistically higher in patients with diastolic dysfunction as compared to those with normal diastolic function (27±26 vs. 11±8 pg/ml, p = 0.03). Conclusion/Significance In conclusion, the combination of diastolic function and BNP measurement adds important information that could help to better stratify patients with Chagas disease.

Non-invasive estimation of pulmonary vascular resistance with cardiac magnetic resonance

AIM To develop a cardiac magnetic resonance (CMR) method for non-invasive estimation of pulmonary vascular resistance (PVR). METHODS AND RESULTS The study comprised 100 consecutive patients with known or suspected pulmonary hypertension (PH; 53 ± 16 years, 73% women) who underwent same-day right heart catheterization (RHC) and CMR. Increased PVR was defined from RHC as >3 WU (n = 66, 66%). From CMR cine and phase-contrast images, right ventricular (RV) volumes and ejection fraction (RVEF), pulmonary artery (PA) flow velocities and areas, and cardiac output were quantified. The best statistical model to estimate PVR was obtained from a derivation cohort (n = 80) based on physiological plausibility and statistical criteria. Validity of the model was assessed in the remaining 20 patients (validation cohort). The CMR-derived model was: estimated PVR (in WU) = 19.38 - [4.62 × Ln PA average velocity (in cm/s)] - [0.08 × RVEF (in %)]. In the validation cohort, the correlation between invasively quantified and CMR-estimated PVR was 0.84 (P < 0.001). The mean bias between the RHC-derived and CMR-estimated PVR was -0.54 (agreement interval -6.02 to 4.94 WU). The CMR model correctly classified 18 (90%) of patients as having normal or increased PVR (area under the receiver operator characteristics curve 0.97; 95% confidence interval: 0.89-1.00). CONCLUSIONS Non-invasive estimation of PVR using CMR is feasible and may be valuable for PH diagnosis and/or follow-up.

Characterization of right ventricular remodeling and failure in a chronic pulmonary hypertension model

In pulmonary hypertension (PH), right ventricular (RV) dysfunction and failure is the main determinant of a poor prognosis. We aimed to characterize RV structural and functional differences during adaptive RV remodeling and progression to RV failure in a large animal model of chronic PH. Postcapillary PH was created surgically in swine (n = 21). After an 8- to 14-wk follow-up, two groups were identified based on the development of overt heart failure (HF): PH-NF (nonfailing, n = 12) and PH-HF (n = 8). In both groups, invasive hemodynamics, pressure-volume relationships, and echocardiography confirmed a significant increase in pulmonary pressures and vascular resistance consistent with PH. Histological analysis also demonstrated distal pulmonary arterial (PA) remodeling in both groups. Diastolic dysfunction, defined by a steeper RV end-diastolic pressure-volume relationship and longitudinal strain, was found in the absence of HF as an early marker of RV remodeling. RV contractility was increased in both groups, and RV-PA coupling was preserved in PH-NF animals but impaired in the PH-HF group. RV hypertrophy was present in PH-HF, although there was evidence of increased RV fibrosis in both PH groups. In the PH-HF group, RV sarcoplasmic reticulum Ca(2+)-ATPase2a expression was decreased, and endoplasmic reticulum stress was increased. Aldosterone levels were also elevated in PH-HF. Thus, in the swine pulmonary vein banding model of chronic postcapillary PH, RV remodeling occurs at the structural, histological, and molecular level. Diastolic dysfunction and fibrosis are present in adaptive RV remodeling, whereas the onset of RV failure is associated with RV-PA uncoupling, defective calcium handling, and hyperaldosteronism.

Diagnostic value of coronary artery calcium scoring in low-intermediate risk patients evaluated in the emergency department for acute coronary syndrome.

Early and accurate triage of patients with possible ischemic chest pain remains challenging in the emergency department because current risk stratification techniques have significant cost and limited availability. The aim of this study was to determine the diagnostic value of the coronary artery calcium score (CACS) for the detection of obstructive coronary artery disease (CAD) in low- to intermediate-risk patients evaluated in the emergency department for suspected acute coronary syndromes. A total of 225 patients presenting to the emergency department with acute chest pain and Thrombolysis In Myocardial Infarction (TIMI) scores <4 who underwent non-contrast- and contrast-enhanced coronary computed tomographic angiography were included. CACS was calculated from the noncontrast scan using the Agatston method. The prevalence of obstructive CAD (defined from the contrast scan as ≥ 50% maximal reduction in luminal diameter in any segment) was 9% and increased significantly with higher scores (p <0.01 for trend). CACS of 0 were observed in 133 patients (59%), of whom only 2 (1.5%) had obstructive CAD. The diagnostic accuracy of CACS to detect obstructive CAD was good, with an area under the receiver-operating characteristic curve of 0.88 and a negative predictive value of 99% for a CACS of 0. In a multivariate model, CACS was independently associated with obstructive CAD (odds ratio 7.01, p = 0.02) and provided additional diagnostic value over traditional CAD risk factors. In conclusion, CACS appears to be an effective initial tool for risk stratification of low- to intermediate-risk patients with possible acute coronary syndromes, on the basis of its high negative predictive value and additive diagnostic value.