A. Lopez-Granados - Academia.edu (original) (raw)

Papers by A. Lopez-Granados

The Journal of Heart and Lung Transplantation, 2014

European Heart Journal 15(ABSTR Suppl. ), Feb 9, 1994

European Heart Journal, 2017

ysis right atrial pressure (RAP), mean pulmonary arterial pressure (mPAP), pulmonary PP, pulmonar... more ysis right atrial pressure (RAP), mean pulmonary arterial pressure (mPAP), pulmonary PP, pulmonary artery wedge pressure (PAWP), cardiac index (CI), SV and PAC were significantly associated with mortality. At ROC analysis PAC presented an AUC of 0.79 (0.69-0.88) in predicting mortality. When inserted into a multivariate Cox regression model only PAC (HR=0.37, CI: 0.16-0.87, p=0.02) and RAP (HR=1.03, CI: 1.01-1.06, p=0.01) were independently associated with worse survival. Conclusion: Impaired PAC yielded a strong and independent prognostic value in a highly selected cohort of patients enlisted for HT. 4995 | BEDSIDE Internal validation of tricuspide annulus plane systolic excursion as a mean of acute rejection diagnosis in heart transplant recipients

European Heart Journal, 2017

Imaging for right ventricular function 289 ment (RVMI) was defined as an elevation greater than 1... more Imaging for right ventricular function 289 ment (RVMI) was defined as an elevation greater than 1 mm in V1 or V4R within 12 hours of symptom onset. Results: Nine patients (11.1%) died during hospitalization and the characteristics of these patients is listed in Table. RV global longitudinal strain (RV-GLS) was significantly lower in these patients and eight of them were presented with RVMI. Multivariate logistic regression analysis including age, sex, pro brain natriuretic peptide (pro-BNP), Thrombolysis In Myocardial Infarction (TIMI) 3 flow, and RV-GLS revealed that age and RV-GLS were independent predictors of in-hospital mortality in patients with acute inferior MI (r2 of the model = 0.629; p<0.001). Conclusions: RV-GLS may be used to determine prognosis and RV involvement in patients with acute inferior MI.

European Heart Journal, 2017

Several studies have identified Copy Number Variants (CNVs) as responsible for cardiac diseases a... more Several studies have identified Copy Number Variants (CNVs) as responsible for cardiac diseases associated with Sudden Cardiac Death (SCD), but very few exhaustive analyses of multiple genes in large cohorts of patients have been performed, and they are generally focused on a specific SCD-related disease. The aim of the present study was to screen for CNVs the 55 or 78 most prevalent genes associated with SCD in a large cohort of patients who suffered sudden unexplained death or had a cardiomyopathy or a channelopathy. A total of 1765 European patients were analyzed with a homemade algorithm for the assessment of CNVs using High Throughput Sequencing data. Thirty-six CNVs were identified (2%), and most of them appeared to have a pathogenic role. The frequency of CNVs among cases of sudden unexplained death, patients with a cardiomyopathy and patients with a channelopathy was 1.4% (8/587), 2.3% (20/874) and 2.6% (8/304), respectively. Detection rates were particularly high for dilated cardiomyopathy (4.4%), arrhythmogenic cardiomyopathy (5.1%) and long QT syndrome (4.7%). As CNVs may underlie a portion of cases with SCD-related diseases, their analysis should be performed as part of the routine genetic testing of these patients. The identification of CNVs (along with Single Nucleotide Variants and small insertions and deletions) will allow the diagnosis confirmation in borderline cases and early management of at-risk family members.

The International Journal of Cardiovascular Imaging, 2020

To investigate the value of tissue Doppler velocities for ruling out treatment-requiring acute ce... more To investigate the value of tissue Doppler velocities for ruling out treatment-requiring acute cellular rejection (TR-ACR), in the context of myocardial deformation analysis performed by means of speckle tracking echocardiography. We performed serial echocardiograms in 37 heart transplant recipients in their first year post-transplantation within 3 h of the routine surveillance endomyocardial biopsies (EMB). The association of the sum of lateral mitral annulus systolic (s′) and early diastolic (e′) velocities, in absolute values, measured by tissue Doppler echocardiography (s′+ e′), with TR-ACR (ACR grade ≥ 2R) was investigated by multivariate analysis, including classic echocardiographic parameters and myocardial deformation variables. A total of 251 pairs of EMB and echo exams were performed, 35 (14%) with rejection grade ≥ 2R (TR-ACR). s′ + e′ was independently associated to TR-ACR (OR 0.80, 95%CI 0.72-0.89, p < 0.0005), with a C statistic of 0.79 (95%CI 0.71-0.87, p < 0.0005) by ROC curve analysis. An s′+ e′ value ≥ 23 cm/s, present in 43% of studies, had a negative predictive value of 98% for ruling out TR-ACR. Moreover, in the same patients, s′+ e′ significantly decreased when TR-ACR occurred after a study without this condition (− 3.7 ± 3.3 cm/s, p = 0.003), but it was similar when rejection status was the same in the present versus the previous study. A drop in s′+ e′ value < 2.7 cm/s from the previous echocardiogram, had a 99% negative predictive value for ruling out TR-ACR. Tissue Doppler velocities, a widely available echo parameter, were found to be a valuable marker for ruling out TR-ACR in this multivariate study which included myocardial deformation variables.

European Heart Journal, Aug 1, 2017

Devices and multidisciplinary interventions in heart failure / Risk prediction for sudden cardiac... more Devices and multidisciplinary interventions in heart failure / Risk prediction for sudden cardiac death and ICD treatments 813 ischemia and cardiac function in patients with ischemic heart failure (IHF). However, complete revascularization is not always achieved in IHF patients undergoing PCI. It remains to be elucidated whether residual stenosis (RS) after PCI impacts on the long-term prognosis of IHF patients, and if so, whether the prognostic impact of RS is influenced by left ventricular (LV) systolic function. Methods: In the present study, we examined 1,307 consecutive stage C/D HF patients with a history of PCI [69.5±11 (SD) years; M/F, 851/456, Stage C/D; 1,287/20] in our Chronic Heart Failure Analysis and Registry in the Tohoku District-2 (CHART-2) Study. We divided them into 2 groups according to the presence or absence of RS (≥75% AHA/ACC classification) at the last coronary angiography. Results: Among the 1,307 subjects, 851 (65.1%) had RS. They were characterized, as compared with those without RS, by a lower proportion of female (18.3 vs. 24.1%, P=0.01), lower levels of hemoglobin (13.1±1.9 vs. 13.5±1.7 g/dl, P<0.01) and estimated glomerular filtration rate (58.4±21.4 vs. 63.1±19.5 ml/min/1.73m 2 , P<0.01), higher levels of brain natriuretic peptide [median (IQR) 93.4 (34.8-231.2) vs. 59.6 (25.6-147.3) pg/ml, P<0.01) and more frequent use of beta-blocker (52.9 vs. 46.7%, P=0.04) and renin-angiotensin system blocker (75.9 vs. 68.0%, P<0.01). In contrast, the prevalences of diabetes mellitus (49.1 vs. 45.2%, P=0.18), previous myocardial infarction (76.5 vs. 80.9%, P=0.07), and left ventricular ejection fraction (LVEF) (56.1±14.2 vs. 56.6±14.1, P=0.62) were comparable between the two groups. During the 3.2±1.3 [SD] years of followup period, all-cause mortality of the patients with RS were significantly higher as compared with those without it [log-rank test; P<0.01, adjusted hazard ratio (HR); 1.64, 95% confidence interval (95% CI); 1.08-2.49, P<0.01]. These results were further confirmed by additional propensity score matching (log-rank test; P<0.01). Furthermore, to reveal the influence of LV systolic function on the prognostic impact of RS, we divided all the subjects into three groups by LVEF [EF<40% (HFrEF; HF with reduced EF), EF 40-50% (borderline EF), and EF≥50% (HF-pEF; HF with preserved EF)]. We found that RS was significantly associated with higher all-cause mortality in patients with HFpEF [HR (95% CI); 1.94 (1.22-3.09), P<0.01] and borderline EF [HR (95% CI); 4.47 (1.13-14.98), P<0.01], but not in those with HFrEF [HR (95% CI); 1.20 (0.59-2.43), P=0.62] (Figure).

Revista clinica espanola, Jan 31, 2017

Heart failure (HF) is currently one of the most significant healthcare problems in Spain and has ... more Heart failure (HF) is currently one of the most significant healthcare problems in Spain and has a continuously increasing prevalence. Advances in our understanding of the various biological responses that promote cardiac remodelling and pulmonary venous congestion constitute the basis of current treatment. This article, prepared by members of the HF groups of the Spanish Society of Cardiology and the Spanish Society of Internal Medicine, discusses the current therapeutic strategies for patients with congestion refractory to diuretic treatment. The article includes our clinical experience with the use of tolvaptan as an additional treatment for congestion associated with hyponatraemia. To this end, we propose an algorithm for the use of tolvaptan in patients with congestive HF, natraemia <130mEq/l and poor response to conventional diuretic treatment.

Transplantation Proceedings, 2003

The aim of this study was to investigate the absorption profile of tacrolimus (TAC) in heart tran... more The aim of this study was to investigate the absorption profile of tacrolimus (TAC) in heart transplant patients in order to find the best sampling time to predict the total exposure and to explore the target range for optimal clinical immunosuppression. Twenty-five full pharmacokinetic studies were performed in 22 heart transplant patients (11 men and 7 women) at less than 1 year posttransplant. The immunosuppressive treatment was steroids plus azathioprine or mycophenolate mofetil and TAC. The mean age was 55 years (36-64 years) and the mean weight 70.49 kg (50-111 kg). After three days of receiving the same dose, eight blood samples were collected at 0.5, 1, 2, 4, 6, 8, and 12 hours postmorning dose. TAC concentrations were measured by microparticle enzyme immunoassay (IMx). Area under the concentration-time curve(AUC 0-12) was calculated by the trapezoidal rule. Using 0-4 hours TAC blood concentrations, a projected 12 hours AUC (extrapolated AUC 0-4) was calculated assuming C 0 and C 12 were comparable. A high interpatient TAC pharmacokinetics variability that was greater during the absorption phase was observed. A Cmax (30.5 Ϯ 13.8 ng/mL) was reached at 2.3 Ϯ 1.5 h. When target trough levels were achieved (10-20 ng/mL), the mean tacrolimus exposure was 230.6 Ϯ 59.2 ng h/mL (120.14-327.7) (n ϭ 19). Correlation between AUC 0-12 and C 0 was relatively good (r 2 ϭ 0.74). Between individual time points, C 4 showed the best correlation (r 2 ϭ 0.88). In any case the best strategy to monitor is to obtain the extrapolated AUC 0-4 (r 2 ϭ 0.98), as a good approach to patients with a poor response to treatment.

Transplantation Proceedings, 2003

The aim of this study was to evaluate cyclosporine (CyA) absorption profiles in heart transplanta... more The aim of this study was to evaluate cyclosporine (CyA) absorption profiles in heart transplantation to establish the most adequate monitoring strategy and determine the optimal therapeutic range for AUC 0-4 or C 2 levels. A total of 22 full pharmacokinetic studies were performed at steady-state in 22 adult heart transplant recipients (18 men, 4 women). Twelve studies were performed during the first month posttransplant (group I), and 10 studies were done after 1 month (group II). In 9 outpatients we performed an abbreviated AUC 0-4. The mean age of the patients was 49 Ϯ 15 years (range, 15-72 years), and the mean weight was 70.4 Ϯ 10.8 kg (mean, 54-98 kg). The CyA dosage had been adjusteded to maintain trough levels (C 0) in the putative target ranges of 200 to 400 ng/mL in group I and between 100 to 300 ng/mL in group II. Blood samples were drawn prior to and at 0.5, 1, 2, 4, 6, 8, and 12 hours after the morning dose. The CyA blood levels were measured by the AxSYM cyclosporine assay. The AUC was calculated by the trapezoidal rule. Multiple linear regression was done to evaluate the predictive ability of various limited sampling strategies. The C 0 correlated poorly, either with the full AUC (r 2 ϭ 0.64) or the AUC 0-4 (r 2 ϭ 0.43), while C 2 seemed to be the most accurate single predictor of drug exposure (r 2 ϭ 0.92 for AUC 0-12 ; r 2 ϭ 0.74 for AUC 0-4). For both AUC 0-4 and AUC 0-12 , all 2-or 3-point strategies had r 2 values approaching that of the C 2 value. In conclusion, C 2 is a simple, fast, and accurate value to predict AUC 0-4 in routine clinical practice. Its implementation must focus on ensuring the commitment of all unit staff, thus ensuring that patients are sampled on time and minimizing the impact on workload.

European Heart Journal, Aug 1, 2017

Cardiovascular physiology 337 these immune cells, we performed PAB on macrophage-depleted mice, C... more Cardiovascular physiology 337 these immune cells, we performed PAB on macrophage-depleted mice, CD4 T cells, CD8 T cells or B cells-knockout mice. Only macrophage-depleted mice developed complete atrio-ventricular block leading to sudden death after PAB while the other mice survived. RNA sequences of various tissue macrophages revealed that secretion factor Amphiregulin (Areg) was specifically expressed in cardiac resident macrophages. We also found that cardiac macrophages were the only source of amphiregulin in the heart, which suggested that amphiregulin could play crucial roles in the specific heart function. To examine whether AREG contributes to cardiac electrical impulse conduction, gap junctional intercellular communication between cardiomyocytes of neonatal mouse was assessed by scrape loading dye transfer assay. AREG increased gap junction formation which was abolished by an EGF receptor inhibitor. In addition, gap junction formation between cultured cardiomyocytes was augmented when co-cultured with cardiac macrophages sorted from wild type mice, but not from Areg-knockout mice. To examine the role of Areg in vivo, we performed PAB on Areg-knockout mice and the mice which underwent bone marrow transplantation from Areg-knockout mice. They also developed atrio-ventricular block and sudden death after PAB. The heart section of Areg-knockout mice showed that the connexin43 (Cx43) was expressed abundantly but failed to localize to intercalated discs. Western blotting revealed that phosphorylation of Cx43 which is important for gap junction formation did not occur when AREG was knocked out. To further clarify the effect of AREG on Cx43, we transfected GFP-tagged Cx43 into HeLa cells. Cx43-GFP assembled into gap junction plaques in the adjoining plasma membrane. AREG administration induced larger gap junction plaques than vehicle whose effect was blocked by the EGF receptor inhibitor. Conclusion: Cardiac macrophages are protective against sudden cardiac death through maintaining cardiac electrical impulse conduction in the setting of the right-sided heart failure. AREG secreted from cardiac macrophages facilitates Cx43 localization to intercalated discs through phosphorylation of Cx43.

European Heart Journal

Background Heart failure (HF) admission is a serious event in the follow up of patients with chro... more Background Heart failure (HF) admission is a serious event in the follow up of patients with chronic coronary syndromes (CCS). Stratification schemes have been described for predicting this end-point but none of them has been externally validated. Purpose To develop point-scores for predicting incident HF admission with data from previous studies, to perform an external validation in an independent prospective cohort study, and to compare their discriminative ability for this event. Methods We performed a literature review searching for prospective studies including patients with CCS, excluding patients with HF at baseline, with data on HF admission incidence in follow up and predictive variables. If undescribed previously, scores were developed including those variables independently associated with this outcome, and score points were assigned based in the relative magnitude of the coefficients of Cox regression models. The resulting scores were validated and their discriminative a...

European Heart Journal

Background In the COMPASS trial, low dose rivaroxaban (2.5 mg/12h) on top of aspirin showed a 26%... more Background In the COMPASS trial, low dose rivaroxaban (2.5 mg/12h) on top of aspirin showed a 26% reduction in major cardiovascular events in patients with stable coronary artery disease (sCAD). However, information about external applicability of these results is limited. Our objective was to assess potential eligibility for this treatment in a “real world” cohort of Spanish patients with sCAD and to evaluate the incidence of major events in the long-term follow up in this population. Methods The CICCOR registry (“Chronic ischemic heart disease in Cordoba”, in Spanish “Cardiopatía isquémica crόnica en Cordoba”) is a prospective, monocentric study. From February 1, 2000 to January 31, 2004, all consecutive patients with sCAD attended at two outpatient cardiology clinics in a city of the south of Spain were included in the study and prospectively followed. The COMPASS inclusion and exclusion criteria were applied to this cohort, and the proportion of patients potentially eligible for...

European Heart Journal - Cardiovascular Imaging

Introduction and purpose Preliminary reports suggests that left atrial longitudinal strain (LALS)... more Introduction and purpose Preliminary reports suggests that left atrial longitudinal strain (LALS) variables are a sensitive marker of acute cellular rejection (ACR) in heart transplant recipients (HTxR), discriminating between those studies without rejection and those with any grade of rejection. Intervendor variability is a concern in the widespread use of this technique. Our objective was to compare the LALS evaluated by two different softwares. Methods From September 2014 to October 2016 we performed, in 18 consecutive adult HTxR in their first year posttransplantation, serial echocardiographic exams within 3 hours of the routine surveillance endomyocardial biopsies (EMB), in a single centre. Peak average longitudinal strain, and strain rate were measured in the left atrium in the apical four chambers view in all studies, using both softwares, its association with the presence of ACR was investigated, and intervendor variability was evaluated. Results a total of 147 pairs of EMB ...

European Heart Journal - Cardiovascular Imaging

Edge-to-edge mitral valve repair (E2E-MVR) has emerged as a therapeutical option in patients with... more Edge-to-edge mitral valve repair (E2E-MVR) has emerged as a therapeutical option in patients with secondary mitral regurgitation (SMR). Two tethering patterns (TP) have been described in SMR: symmetric and asymmetric. However, information on the implications of these TP on E2E-MVR is limited. Our aim was to assess the impact of mitral valve TP on clinical, echocardiographic and procedure-related characteristics in patients undergoing E2E-MVR. We consecutively recruited 62 patients with at least moderate SMR who underwent E2E-MVR in our center between 2011 and 2019 and analysed clinical, echocardiographic and procedure-related characteristics according to TP, which we classified into symmetric and asymmetric considering jet direction and mitral valve leaflet position during systole by means of two-dimensional transesophageal echocardiography (Figure 1). In our series, 43 patients (69.3%) had symmetric TP and 19 (30.7%) had asymmetric TP. Asymmetric TP was associated with ischemic aet...

European Heart Journal

Background Safety trials of antidiabetic drugs have included a main endpoint of cardiovascular mo... more Background Safety trials of antidiabetic drugs have included a main endpoint of cardiovascular morbidity and mortality. However, “real world” data on long term prognosis of diabetic patients with stable coronary artery disease (sCAD) are limited. This study aimed to assess long-term incidence of major cardiovascular events in this population and to identify clinical predictors of this end-point. Methods The CICCOR registry is a prospective, monocentric, cohort study. From February 1, 2000 to January 31, 2004, all consecutive patients with sCAD attended at two outpatient cardiology clinics in a city of the south of Spain were included in the study and prospectively followed. Patients with type 2 diabetes mellitus were selected for this analysis. None of these patients received sodium-glucose cotransporter-2 inhibitors at first visit, as they were not commercially available at that time. Survival free of major cardiovascular events (combined end-point: acute myocardial infarction, str...

European Heart Journal

Background: Left ventricular (LV) twisting motion assists in ejecting blood from the LV during sy... more Background: Left ventricular (LV) twisting motion assists in ejecting blood from the LV during systole, while the untwisting motion, through the release of stored elastic energy, may contribute to early diastolic suction. No prior studies have evaluated changes in LV twist following balloon mitral valvuloplasty (BMV). Purpose: To describe changes in LV rotational deformation in patients with rheumatic mitral stenosis (MS) using cardiac magnetic resonance imaging (CMR) 6 months and one year after successful BMV. Methods: Thirty patients (median age 33 years, 22 women) with isolated severe rheumatic MS were studied. CMR myocardial tissue tagging was used for assessment of LV rotational deformation. LV twist was defined as the net difference between apical counterclockwise and basal clockwise rotation. To make the values comparable among different sizes ventricles, LV torsion was calculated as the twist value normalized to the length of the ventricle and multiplied by the mean radius at the base and apex. LV torsion was assessed at base-apex and basemid levels. All patients had CMR studies before, 6 months and one year after successful BMV. Results: At baseline, patients had a mitral valve area of 0.9 (0.6-1.3) cm 2 , mean pressure gradient of 12.5 (8-24) mmHg across the mitral valve and LV ejection fraction (LVEF) of 57 (range: 45-69) %. Analysis of LV rotational deformation showed significant improvement in LV baseapex torsion at 6 months (3.3°vs. 2.5°, p<0.001) with a further improvement at one year (4.1°vs. 3.3°, p=0.05) following BMV. Similar pattern of change was seen in LV base-mid torsion with a significant increase at 6 months (3.6°v s.2.3°, p<0.001) and a further increase at one year (4.7°vs. 3.6°, p=0.007). These changes were associated with a significant increase in LVEF (62% vs. 57%, p<0.001) at one year following BMV. Conclusions: Among patients with isolated rheumatic severe MS, successful BMV is associated with a significant improvement in LV rotational deformation that is accompanied by a significant improvement in LV ejection fraction.

European Heart Journal – Cardiovascular Imaging, 2016

Background: To evaluate the interventricular cardiac relationship, Doppler measurement of Qp/Qs b... more Background: To evaluate the interventricular cardiac relationship, Doppler measurement of Qp/Qs by transthoracic echocardiography (TTE) has been used. It is complicated to do, however, and cannot evaluate interventricular relationship in the same cardiac phase. In recent echocardiographic examination, TAPSE (tricuspid annular plane of systolic excursion) and MAPSE (mitral annular plane of systolic excursion) have become widely used to assessment and quantification of the ventricular function. TAPSE and MAPSE can be evaluated using single echocardiographic view of four chamber view, but could not be evaluate in same cardiac cycle until the speckle tracking method introduce. To conquer this problem, we suppose to use the speckle tracking method. Speckle tracking method is an image analyzing technique to trace the local speckle pattern in B-mode of TTE. In practice, on simply placing ROI (region of interesting) to both the lateral tricuspid annulus and the lateral mitral annulus, based to apex, we will be able to evaluate TAPSE and MAPSE in the same cardiac cycle. We have hypothesized these; 1) the relationship of TAPSE and MAPSE in the same cardiac cycle could be a new surrogate indicator of interventricular functional relationship or dyssynchrony. 2) In AS patients, this relation could be different from healthy individuals. Purpose: This study was conducted to evaluate whether the relationship of TAPSE and MAPSE on the same cardiac cycle using the speckle tracking method could be a indicator of interventricular relationship in the patients with severe aortic stenosis. Methods: This study has been approved by our institutional review board. We prospectively recruited 20 healthy adult volunteers and 20 patients with severe AS that were indicated for TAVI. Using TTE, we measured TAPSE and MAPSE with speckle tracking method under a resting condition in addition to standard measurements. We analyzed maximum distance and duration time of tricuspid and mitral annular displacement in trans-apical 4ch view by Q-LABV R (Phillips electronicsV C) and a2DQ (auto 2D quantification) software in EPIQ 7G(Phillips electronicsV C). Statistical analysis was made with ANOVA and the Pearson's correlation analysis, and p < 0.05 was considered significant. Result: Healthy adult volunteers have no difference in TAPSE and MAPSE time phase (p ¼ 0.1516). Severe AS patients have restricted MAPSE (p ¼ 4.331*10-10) and retracted time phase (p ¼ 0.0014). (Figure) Conclusion: This study showed that the large interventricular mismatch in cardiac time phase has occurred in severe AS patients whereas not in healthy volunteers. The time phase deviation between TAPSE and MAPSE might become one of the possible indicators of the severity in a reduced ventricular function.

The Journal of Heart and Lung Transplantation, 2014

European Heart Journal 15(ABSTR Suppl. ), Feb 9, 1994

European Heart Journal, 2017

ysis right atrial pressure (RAP), mean pulmonary arterial pressure (mPAP), pulmonary PP, pulmonar... more ysis right atrial pressure (RAP), mean pulmonary arterial pressure (mPAP), pulmonary PP, pulmonary artery wedge pressure (PAWP), cardiac index (CI), SV and PAC were significantly associated with mortality. At ROC analysis PAC presented an AUC of 0.79 (0.69-0.88) in predicting mortality. When inserted into a multivariate Cox regression model only PAC (HR=0.37, CI: 0.16-0.87, p=0.02) and RAP (HR=1.03, CI: 1.01-1.06, p=0.01) were independently associated with worse survival. Conclusion: Impaired PAC yielded a strong and independent prognostic value in a highly selected cohort of patients enlisted for HT. 4995 | BEDSIDE Internal validation of tricuspide annulus plane systolic excursion as a mean of acute rejection diagnosis in heart transplant recipients

European Heart Journal, 2017

Imaging for right ventricular function 289 ment (RVMI) was defined as an elevation greater than 1... more Imaging for right ventricular function 289 ment (RVMI) was defined as an elevation greater than 1 mm in V1 or V4R within 12 hours of symptom onset. Results: Nine patients (11.1%) died during hospitalization and the characteristics of these patients is listed in Table. RV global longitudinal strain (RV-GLS) was significantly lower in these patients and eight of them were presented with RVMI. Multivariate logistic regression analysis including age, sex, pro brain natriuretic peptide (pro-BNP), Thrombolysis In Myocardial Infarction (TIMI) 3 flow, and RV-GLS revealed that age and RV-GLS were independent predictors of in-hospital mortality in patients with acute inferior MI (r2 of the model = 0.629; p<0.001). Conclusions: RV-GLS may be used to determine prognosis and RV involvement in patients with acute inferior MI.

European Heart Journal, 2017

Several studies have identified Copy Number Variants (CNVs) as responsible for cardiac diseases a... more Several studies have identified Copy Number Variants (CNVs) as responsible for cardiac diseases associated with Sudden Cardiac Death (SCD), but very few exhaustive analyses of multiple genes in large cohorts of patients have been performed, and they are generally focused on a specific SCD-related disease. The aim of the present study was to screen for CNVs the 55 or 78 most prevalent genes associated with SCD in a large cohort of patients who suffered sudden unexplained death or had a cardiomyopathy or a channelopathy. A total of 1765 European patients were analyzed with a homemade algorithm for the assessment of CNVs using High Throughput Sequencing data. Thirty-six CNVs were identified (2%), and most of them appeared to have a pathogenic role. The frequency of CNVs among cases of sudden unexplained death, patients with a cardiomyopathy and patients with a channelopathy was 1.4% (8/587), 2.3% (20/874) and 2.6% (8/304), respectively. Detection rates were particularly high for dilated cardiomyopathy (4.4%), arrhythmogenic cardiomyopathy (5.1%) and long QT syndrome (4.7%). As CNVs may underlie a portion of cases with SCD-related diseases, their analysis should be performed as part of the routine genetic testing of these patients. The identification of CNVs (along with Single Nucleotide Variants and small insertions and deletions) will allow the diagnosis confirmation in borderline cases and early management of at-risk family members.

The International Journal of Cardiovascular Imaging, 2020

To investigate the value of tissue Doppler velocities for ruling out treatment-requiring acute ce... more To investigate the value of tissue Doppler velocities for ruling out treatment-requiring acute cellular rejection (TR-ACR), in the context of myocardial deformation analysis performed by means of speckle tracking echocardiography. We performed serial echocardiograms in 37 heart transplant recipients in their first year post-transplantation within 3 h of the routine surveillance endomyocardial biopsies (EMB). The association of the sum of lateral mitral annulus systolic (s′) and early diastolic (e′) velocities, in absolute values, measured by tissue Doppler echocardiography (s′+ e′), with TR-ACR (ACR grade ≥ 2R) was investigated by multivariate analysis, including classic echocardiographic parameters and myocardial deformation variables. A total of 251 pairs of EMB and echo exams were performed, 35 (14%) with rejection grade ≥ 2R (TR-ACR). s′ + e′ was independently associated to TR-ACR (OR 0.80, 95%CI 0.72-0.89, p < 0.0005), with a C statistic of 0.79 (95%CI 0.71-0.87, p < 0.0005) by ROC curve analysis. An s′+ e′ value ≥ 23 cm/s, present in 43% of studies, had a negative predictive value of 98% for ruling out TR-ACR. Moreover, in the same patients, s′+ e′ significantly decreased when TR-ACR occurred after a study without this condition (− 3.7 ± 3.3 cm/s, p = 0.003), but it was similar when rejection status was the same in the present versus the previous study. A drop in s′+ e′ value < 2.7 cm/s from the previous echocardiogram, had a 99% negative predictive value for ruling out TR-ACR. Tissue Doppler velocities, a widely available echo parameter, were found to be a valuable marker for ruling out TR-ACR in this multivariate study which included myocardial deformation variables.

European Heart Journal, Aug 1, 2017

Devices and multidisciplinary interventions in heart failure / Risk prediction for sudden cardiac... more Devices and multidisciplinary interventions in heart failure / Risk prediction for sudden cardiac death and ICD treatments 813 ischemia and cardiac function in patients with ischemic heart failure (IHF). However, complete revascularization is not always achieved in IHF patients undergoing PCI. It remains to be elucidated whether residual stenosis (RS) after PCI impacts on the long-term prognosis of IHF patients, and if so, whether the prognostic impact of RS is influenced by left ventricular (LV) systolic function. Methods: In the present study, we examined 1,307 consecutive stage C/D HF patients with a history of PCI [69.5±11 (SD) years; M/F, 851/456, Stage C/D; 1,287/20] in our Chronic Heart Failure Analysis and Registry in the Tohoku District-2 (CHART-2) Study. We divided them into 2 groups according to the presence or absence of RS (≥75% AHA/ACC classification) at the last coronary angiography. Results: Among the 1,307 subjects, 851 (65.1%) had RS. They were characterized, as compared with those without RS, by a lower proportion of female (18.3 vs. 24.1%, P=0.01), lower levels of hemoglobin (13.1±1.9 vs. 13.5±1.7 g/dl, P<0.01) and estimated glomerular filtration rate (58.4±21.4 vs. 63.1±19.5 ml/min/1.73m 2 , P<0.01), higher levels of brain natriuretic peptide [median (IQR) 93.4 (34.8-231.2) vs. 59.6 (25.6-147.3) pg/ml, P<0.01) and more frequent use of beta-blocker (52.9 vs. 46.7%, P=0.04) and renin-angiotensin system blocker (75.9 vs. 68.0%, P<0.01). In contrast, the prevalences of diabetes mellitus (49.1 vs. 45.2%, P=0.18), previous myocardial infarction (76.5 vs. 80.9%, P=0.07), and left ventricular ejection fraction (LVEF) (56.1±14.2 vs. 56.6±14.1, P=0.62) were comparable between the two groups. During the 3.2±1.3 [SD] years of followup period, all-cause mortality of the patients with RS were significantly higher as compared with those without it [log-rank test; P<0.01, adjusted hazard ratio (HR); 1.64, 95% confidence interval (95% CI); 1.08-2.49, P<0.01]. These results were further confirmed by additional propensity score matching (log-rank test; P<0.01). Furthermore, to reveal the influence of LV systolic function on the prognostic impact of RS, we divided all the subjects into three groups by LVEF [EF<40% (HFrEF; HF with reduced EF), EF 40-50% (borderline EF), and EF≥50% (HF-pEF; HF with preserved EF)]. We found that RS was significantly associated with higher all-cause mortality in patients with HFpEF [HR (95% CI); 1.94 (1.22-3.09), P<0.01] and borderline EF [HR (95% CI); 4.47 (1.13-14.98), P<0.01], but not in those with HFrEF [HR (95% CI); 1.20 (0.59-2.43), P=0.62] (Figure).

Revista clinica espanola, Jan 31, 2017

Heart failure (HF) is currently one of the most significant healthcare problems in Spain and has ... more Heart failure (HF) is currently one of the most significant healthcare problems in Spain and has a continuously increasing prevalence. Advances in our understanding of the various biological responses that promote cardiac remodelling and pulmonary venous congestion constitute the basis of current treatment. This article, prepared by members of the HF groups of the Spanish Society of Cardiology and the Spanish Society of Internal Medicine, discusses the current therapeutic strategies for patients with congestion refractory to diuretic treatment. The article includes our clinical experience with the use of tolvaptan as an additional treatment for congestion associated with hyponatraemia. To this end, we propose an algorithm for the use of tolvaptan in patients with congestive HF, natraemia <130mEq/l and poor response to conventional diuretic treatment.

Transplantation Proceedings, 2003

The aim of this study was to investigate the absorption profile of tacrolimus (TAC) in heart tran... more The aim of this study was to investigate the absorption profile of tacrolimus (TAC) in heart transplant patients in order to find the best sampling time to predict the total exposure and to explore the target range for optimal clinical immunosuppression. Twenty-five full pharmacokinetic studies were performed in 22 heart transplant patients (11 men and 7 women) at less than 1 year posttransplant. The immunosuppressive treatment was steroids plus azathioprine or mycophenolate mofetil and TAC. The mean age was 55 years (36-64 years) and the mean weight 70.49 kg (50-111 kg). After three days of receiving the same dose, eight blood samples were collected at 0.5, 1, 2, 4, 6, 8, and 12 hours postmorning dose. TAC concentrations were measured by microparticle enzyme immunoassay (IMx). Area under the concentration-time curve(AUC 0-12) was calculated by the trapezoidal rule. Using 0-4 hours TAC blood concentrations, a projected 12 hours AUC (extrapolated AUC 0-4) was calculated assuming C 0 and C 12 were comparable. A high interpatient TAC pharmacokinetics variability that was greater during the absorption phase was observed. A Cmax (30.5 Ϯ 13.8 ng/mL) was reached at 2.3 Ϯ 1.5 h. When target trough levels were achieved (10-20 ng/mL), the mean tacrolimus exposure was 230.6 Ϯ 59.2 ng h/mL (120.14-327.7) (n ϭ 19). Correlation between AUC 0-12 and C 0 was relatively good (r 2 ϭ 0.74). Between individual time points, C 4 showed the best correlation (r 2 ϭ 0.88). In any case the best strategy to monitor is to obtain the extrapolated AUC 0-4 (r 2 ϭ 0.98), as a good approach to patients with a poor response to treatment.

Transplantation Proceedings, 2003

The aim of this study was to evaluate cyclosporine (CyA) absorption profiles in heart transplanta... more The aim of this study was to evaluate cyclosporine (CyA) absorption profiles in heart transplantation to establish the most adequate monitoring strategy and determine the optimal therapeutic range for AUC 0-4 or C 2 levels. A total of 22 full pharmacokinetic studies were performed at steady-state in 22 adult heart transplant recipients (18 men, 4 women). Twelve studies were performed during the first month posttransplant (group I), and 10 studies were done after 1 month (group II). In 9 outpatients we performed an abbreviated AUC 0-4. The mean age of the patients was 49 Ϯ 15 years (range, 15-72 years), and the mean weight was 70.4 Ϯ 10.8 kg (mean, 54-98 kg). The CyA dosage had been adjusteded to maintain trough levels (C 0) in the putative target ranges of 200 to 400 ng/mL in group I and between 100 to 300 ng/mL in group II. Blood samples were drawn prior to and at 0.5, 1, 2, 4, 6, 8, and 12 hours after the morning dose. The CyA blood levels were measured by the AxSYM cyclosporine assay. The AUC was calculated by the trapezoidal rule. Multiple linear regression was done to evaluate the predictive ability of various limited sampling strategies. The C 0 correlated poorly, either with the full AUC (r 2 ϭ 0.64) or the AUC 0-4 (r 2 ϭ 0.43), while C 2 seemed to be the most accurate single predictor of drug exposure (r 2 ϭ 0.92 for AUC 0-12 ; r 2 ϭ 0.74 for AUC 0-4). For both AUC 0-4 and AUC 0-12 , all 2-or 3-point strategies had r 2 values approaching that of the C 2 value. In conclusion, C 2 is a simple, fast, and accurate value to predict AUC 0-4 in routine clinical practice. Its implementation must focus on ensuring the commitment of all unit staff, thus ensuring that patients are sampled on time and minimizing the impact on workload.

European Heart Journal, Aug 1, 2017

Cardiovascular physiology 337 these immune cells, we performed PAB on macrophage-depleted mice, C... more Cardiovascular physiology 337 these immune cells, we performed PAB on macrophage-depleted mice, CD4 T cells, CD8 T cells or B cells-knockout mice. Only macrophage-depleted mice developed complete atrio-ventricular block leading to sudden death after PAB while the other mice survived. RNA sequences of various tissue macrophages revealed that secretion factor Amphiregulin (Areg) was specifically expressed in cardiac resident macrophages. We also found that cardiac macrophages were the only source of amphiregulin in the heart, which suggested that amphiregulin could play crucial roles in the specific heart function. To examine whether AREG contributes to cardiac electrical impulse conduction, gap junctional intercellular communication between cardiomyocytes of neonatal mouse was assessed by scrape loading dye transfer assay. AREG increased gap junction formation which was abolished by an EGF receptor inhibitor. In addition, gap junction formation between cultured cardiomyocytes was augmented when co-cultured with cardiac macrophages sorted from wild type mice, but not from Areg-knockout mice. To examine the role of Areg in vivo, we performed PAB on Areg-knockout mice and the mice which underwent bone marrow transplantation from Areg-knockout mice. They also developed atrio-ventricular block and sudden death after PAB. The heart section of Areg-knockout mice showed that the connexin43 (Cx43) was expressed abundantly but failed to localize to intercalated discs. Western blotting revealed that phosphorylation of Cx43 which is important for gap junction formation did not occur when AREG was knocked out. To further clarify the effect of AREG on Cx43, we transfected GFP-tagged Cx43 into HeLa cells. Cx43-GFP assembled into gap junction plaques in the adjoining plasma membrane. AREG administration induced larger gap junction plaques than vehicle whose effect was blocked by the EGF receptor inhibitor. Conclusion: Cardiac macrophages are protective against sudden cardiac death through maintaining cardiac electrical impulse conduction in the setting of the right-sided heart failure. AREG secreted from cardiac macrophages facilitates Cx43 localization to intercalated discs through phosphorylation of Cx43.

European Heart Journal

Background Heart failure (HF) admission is a serious event in the follow up of patients with chro... more Background Heart failure (HF) admission is a serious event in the follow up of patients with chronic coronary syndromes (CCS). Stratification schemes have been described for predicting this end-point but none of them has been externally validated. Purpose To develop point-scores for predicting incident HF admission with data from previous studies, to perform an external validation in an independent prospective cohort study, and to compare their discriminative ability for this event. Methods We performed a literature review searching for prospective studies including patients with CCS, excluding patients with HF at baseline, with data on HF admission incidence in follow up and predictive variables. If undescribed previously, scores were developed including those variables independently associated with this outcome, and score points were assigned based in the relative magnitude of the coefficients of Cox regression models. The resulting scores were validated and their discriminative a...

European Heart Journal

Background In the COMPASS trial, low dose rivaroxaban (2.5 mg/12h) on top of aspirin showed a 26%... more Background In the COMPASS trial, low dose rivaroxaban (2.5 mg/12h) on top of aspirin showed a 26% reduction in major cardiovascular events in patients with stable coronary artery disease (sCAD). However, information about external applicability of these results is limited. Our objective was to assess potential eligibility for this treatment in a “real world” cohort of Spanish patients with sCAD and to evaluate the incidence of major events in the long-term follow up in this population. Methods The CICCOR registry (“Chronic ischemic heart disease in Cordoba”, in Spanish “Cardiopatía isquémica crόnica en Cordoba”) is a prospective, monocentric study. From February 1, 2000 to January 31, 2004, all consecutive patients with sCAD attended at two outpatient cardiology clinics in a city of the south of Spain were included in the study and prospectively followed. The COMPASS inclusion and exclusion criteria were applied to this cohort, and the proportion of patients potentially eligible for...

European Heart Journal - Cardiovascular Imaging

Introduction and purpose Preliminary reports suggests that left atrial longitudinal strain (LALS)... more Introduction and purpose Preliminary reports suggests that left atrial longitudinal strain (LALS) variables are a sensitive marker of acute cellular rejection (ACR) in heart transplant recipients (HTxR), discriminating between those studies without rejection and those with any grade of rejection. Intervendor variability is a concern in the widespread use of this technique. Our objective was to compare the LALS evaluated by two different softwares. Methods From September 2014 to October 2016 we performed, in 18 consecutive adult HTxR in their first year posttransplantation, serial echocardiographic exams within 3 hours of the routine surveillance endomyocardial biopsies (EMB), in a single centre. Peak average longitudinal strain, and strain rate were measured in the left atrium in the apical four chambers view in all studies, using both softwares, its association with the presence of ACR was investigated, and intervendor variability was evaluated. Results a total of 147 pairs of EMB ...

European Heart Journal - Cardiovascular Imaging

Edge-to-edge mitral valve repair (E2E-MVR) has emerged as a therapeutical option in patients with... more Edge-to-edge mitral valve repair (E2E-MVR) has emerged as a therapeutical option in patients with secondary mitral regurgitation (SMR). Two tethering patterns (TP) have been described in SMR: symmetric and asymmetric. However, information on the implications of these TP on E2E-MVR is limited. Our aim was to assess the impact of mitral valve TP on clinical, echocardiographic and procedure-related characteristics in patients undergoing E2E-MVR. We consecutively recruited 62 patients with at least moderate SMR who underwent E2E-MVR in our center between 2011 and 2019 and analysed clinical, echocardiographic and procedure-related characteristics according to TP, which we classified into symmetric and asymmetric considering jet direction and mitral valve leaflet position during systole by means of two-dimensional transesophageal echocardiography (Figure 1). In our series, 43 patients (69.3%) had symmetric TP and 19 (30.7%) had asymmetric TP. Asymmetric TP was associated with ischemic aet...

European Heart Journal

Background Safety trials of antidiabetic drugs have included a main endpoint of cardiovascular mo... more Background Safety trials of antidiabetic drugs have included a main endpoint of cardiovascular morbidity and mortality. However, “real world” data on long term prognosis of diabetic patients with stable coronary artery disease (sCAD) are limited. This study aimed to assess long-term incidence of major cardiovascular events in this population and to identify clinical predictors of this end-point. Methods The CICCOR registry is a prospective, monocentric, cohort study. From February 1, 2000 to January 31, 2004, all consecutive patients with sCAD attended at two outpatient cardiology clinics in a city of the south of Spain were included in the study and prospectively followed. Patients with type 2 diabetes mellitus were selected for this analysis. None of these patients received sodium-glucose cotransporter-2 inhibitors at first visit, as they were not commercially available at that time. Survival free of major cardiovascular events (combined end-point: acute myocardial infarction, str...

European Heart Journal

Background: Left ventricular (LV) twisting motion assists in ejecting blood from the LV during sy... more Background: Left ventricular (LV) twisting motion assists in ejecting blood from the LV during systole, while the untwisting motion, through the release of stored elastic energy, may contribute to early diastolic suction. No prior studies have evaluated changes in LV twist following balloon mitral valvuloplasty (BMV). Purpose: To describe changes in LV rotational deformation in patients with rheumatic mitral stenosis (MS) using cardiac magnetic resonance imaging (CMR) 6 months and one year after successful BMV. Methods: Thirty patients (median age 33 years, 22 women) with isolated severe rheumatic MS were studied. CMR myocardial tissue tagging was used for assessment of LV rotational deformation. LV twist was defined as the net difference between apical counterclockwise and basal clockwise rotation. To make the values comparable among different sizes ventricles, LV torsion was calculated as the twist value normalized to the length of the ventricle and multiplied by the mean radius at the base and apex. LV torsion was assessed at base-apex and basemid levels. All patients had CMR studies before, 6 months and one year after successful BMV. Results: At baseline, patients had a mitral valve area of 0.9 (0.6-1.3) cm 2 , mean pressure gradient of 12.5 (8-24) mmHg across the mitral valve and LV ejection fraction (LVEF) of 57 (range: 45-69) %. Analysis of LV rotational deformation showed significant improvement in LV baseapex torsion at 6 months (3.3°vs. 2.5°, p<0.001) with a further improvement at one year (4.1°vs. 3.3°, p=0.05) following BMV. Similar pattern of change was seen in LV base-mid torsion with a significant increase at 6 months (3.6°v s.2.3°, p<0.001) and a further increase at one year (4.7°vs. 3.6°, p=0.007). These changes were associated with a significant increase in LVEF (62% vs. 57%, p<0.001) at one year following BMV. Conclusions: Among patients with isolated rheumatic severe MS, successful BMV is associated with a significant improvement in LV rotational deformation that is accompanied by a significant improvement in LV ejection fraction.

European Heart Journal – Cardiovascular Imaging, 2016

Background: To evaluate the interventricular cardiac relationship, Doppler measurement of Qp/Qs b... more Background: To evaluate the interventricular cardiac relationship, Doppler measurement of Qp/Qs by transthoracic echocardiography (TTE) has been used. It is complicated to do, however, and cannot evaluate interventricular relationship in the same cardiac phase. In recent echocardiographic examination, TAPSE (tricuspid annular plane of systolic excursion) and MAPSE (mitral annular plane of systolic excursion) have become widely used to assessment and quantification of the ventricular function. TAPSE and MAPSE can be evaluated using single echocardiographic view of four chamber view, but could not be evaluate in same cardiac cycle until the speckle tracking method introduce. To conquer this problem, we suppose to use the speckle tracking method. Speckle tracking method is an image analyzing technique to trace the local speckle pattern in B-mode of TTE. In practice, on simply placing ROI (region of interesting) to both the lateral tricuspid annulus and the lateral mitral annulus, based to apex, we will be able to evaluate TAPSE and MAPSE in the same cardiac cycle. We have hypothesized these; 1) the relationship of TAPSE and MAPSE in the same cardiac cycle could be a new surrogate indicator of interventricular functional relationship or dyssynchrony. 2) In AS patients, this relation could be different from healthy individuals. Purpose: This study was conducted to evaluate whether the relationship of TAPSE and MAPSE on the same cardiac cycle using the speckle tracking method could be a indicator of interventricular relationship in the patients with severe aortic stenosis. Methods: This study has been approved by our institutional review board. We prospectively recruited 20 healthy adult volunteers and 20 patients with severe AS that were indicated for TAVI. Using TTE, we measured TAPSE and MAPSE with speckle tracking method under a resting condition in addition to standard measurements. We analyzed maximum distance and duration time of tricuspid and mitral annular displacement in trans-apical 4ch view by Q-LABV R (Phillips electronicsV C) and a2DQ (auto 2D quantification) software in EPIQ 7G(Phillips electronicsV C). Statistical analysis was made with ANOVA and the Pearson's correlation analysis, and p < 0.05 was considered significant. Result: Healthy adult volunteers have no difference in TAPSE and MAPSE time phase (p ¼ 0.1516). Severe AS patients have restricted MAPSE (p ¼ 4.331*10-10) and retracted time phase (p ¼ 0.0014). (Figure) Conclusion: This study showed that the large interventricular mismatch in cardiac time phase has occurred in severe AS patients whereas not in healthy volunteers. The time phase deviation between TAPSE and MAPSE might become one of the possible indicators of the severity in a reduced ventricular function.