Risk Assessment after ST-Segment Elevation Myocardial Infarction : can Biomarkers Improve the Performance of Clinical Variables?

Introduction: Myocardial infarction with ST-segment elevation (STEMI) is the coronary artery disease associated with the highest risk of morbimortality; however, this risk is heterogeneous, usually being evaluated by clinical scores. Risk assessment is a key factor in personalized clinical management of patients with this disease. Aim: The aim of this study was to assess whether some new cardiac biomarkers considered alone, combined in a multibiomarker model or in association with clinical variables, improve the short- and long-term risk stratification of STEMI patients. Materials and Methods: This was a retrospective observational study of 253 patients with STEMI. Blood samples were obtained before or during the angiography. The assessed biomarkers were C-terminal fragment of insulin-like growth factor binding protein-4 (CT-IGFBP4), high sensitive cardiac troponin T (hs-cTnT), N-terminal fragment of probrain natriuretic peptide (NT-proBNP), and growth differentiation factor 15 (GDF-15); they reflect different cardiovascular (CV) physiopathological pathways and underlying pathologies. We registered in-hospital and follow-up mortalities and their causes (cardiovascular and all-cause) and major adverse cardiac events (MACE) during a two year follow-up. Discrimination, survival analysis, model calibration, and reclassification of the biomarkers were comprehensively evaluated. Results and Discussion: In total, 55 patients (21.7%) died, 33 in-hospital and 22 during the follow-up, most of them (69.1%) from CV causes; 37 MACE occurred during follow-up. Biomarkers showed good prognostic ability to predict mortality, alone and combined with the multibiomarker model. A predictive clinical model based on age, Killip-Kimball class, estimated glomerular filtration rate (eGFR), and heart rate was derived by multivariate analysis. GDF-15 and NT-proBNP significantly improved risk assessment of the clinical model, as shown by discrimination, calibration, and reclassification of all the end-points except for all-cause mortality. The combination of NT-proBNP and hs-cTnT improved CV mortality prediction. Conclusions: GDF-15 and NT-proBNP added value to the usual risk assessment of STEMI patients

Soluble urokinase-type plasminogen activator receptor improves early risk stratification in cardiogenic shock

Aims Soluble urokinase-type plasminogen activator receptor (suPAR) is a biomarker reflecting the level of immune activation. It has been shown to have prognostic value in acute coronary syndrome and heart failure as well as in critical illness. Considering the complex pathophysiology of cardiogenic shock (CS), we hypothesized suPAR might have prognostic properties in CS as well. The aim of this study was to assess the kinetics and prognostic utility of suPAR in CS. Methods and results SuPAR levels were determined in serial plasma samples (0-96 h) from 161 CS patients in the prospective, observational, multicentre CardShock study. Kinetics of suPAR, its association with 90-day mortality, and additional value in risk-stratification were investigated. The median suPAR-level at baseline was 4.4 [interquartile range (IQR) 3.2-6.6)] ng/mL. SuPAR levels above median were associated with underlying comorbidities, biomarkers reflecting renal and cardiac dysfunction, and higher 90-day mortality (49% vs. 31%; P = 0.02). Serial measurements showed that survivors had significantly lower suPAR levels at all time points compared with nonsurvivors. For risk stratification, suPAR at 12 h (suPAR(12h)) with a cut-off of 4.4 ng/mL was strongly associated with mortality independently of established risk factors in CS: OR 5.6 (95% CI 2.0-15.5); P = 0.001) for death by 90 days. Adding suPAR(12h) > 4.4 ng/mL to the CardShock risk score improved discrimination identifying high-risk patients originally categorized in the intermediate-risk category. Conclusion SuPAR associates with mortality and improves risk stratification independently of other previously known risk factors in CS patients.Peer reviewe

Adrenomedullin : a marker of impaired hemodynamics, organ dysfunction, and poor prognosis in cardiogenic shock

Background: The clinical CardShock risk score, including baseline lactate levels, was recently shown to facilitate risk stratification in patients with cardiogenic shock (CS). As based on baseline parameters, however, it may not reflect the change in mortality risk in response to initial therapies. Adrenomedullin is a prognostic biomarker in several cardiovascular diseases and was recently shown to associate with hemodynamic instability in patients with septic shock. The aim of our study was to evaluate the prognostic value and association with hemodynamic parameters of bioactive adrenomedullin (bio-ADM) in patients with CS. Methods: CardShock was a prospective, observational, European multinational cohort study of CS. In this sub-analysis, serial plasma bio-ADM and arterial blood lactate measurements were collected from 178 patients during the first 10 days after detection of CS. Results: Both bio-ADM and lactate were higher in 90-day non-survivors compared to survivors at all time points (P <0.05 for all). Lactate showed good prognostic value during the initial 24 h (AUC 0.78 at admission and 0.76 at 24 h). Subsequently, lactate returned normal ( 55.7 pg/mL) at 48 h compared to those with low bio-ADM levels (49.1 vs. 22.6%, P = 0.001). High levels of bio-ADM were associated with impaired cardiac index, mean arterial pressure, central venous pressure, and systolic pulmonary artery pressure during the study period. Furthermore, high levels of bio-ADM at 48 to 96 h were related to persistently impaired cardiac and end-organ function. Conclusions: Bio-ADM is a valuable prognosticator and marker of impaired hemodynamics in CS patients. High levels of bio-ADM may show shock refractoriness and developing end-organ dysfunction and thus help to guide therapeutic approach in patients with CS.Peer reviewe

Anemia in patients with high-risk acute coronary syndromes admitted to Intensive Cardiac Care Units

Little information exists about the role of anemia in patients with acute coronary syndromes (ACS) admitted to Intensive Cardiac Care Units (ICCU). The aim of this study was to assess the prevalence of anemia and its impact on management and outcomes in this clinical setting. All consecutive patients admitted to eight different ICCUs with diagnosis of non-ST segment elevation ACS (NSTEACS) were prospectively included. Anemia was defined as hemoglobin < 130 g/L in men and < 120 g/L in women. The association between anemia and mortality or readmission at six months was assessed by the Cox regression method. A total of 629 patients were included. Mean age was 66.6 years. A total of 197 patients (31.3%) had anemia. Coronary angiography was performed in most patients (96.2%). Patients with anemia were significantly older, with a higher prevalence of comorbidities, poorer left ventricle ejection fraction and higher GRACE score values. Patients with anemia underwent less often coronary angiography, but underwent more often intraaortic counterpulsation, non-invasive mechanical ventilation and renal replacement therapies. Both ICCU and hospital stay were significantly longer in patients with anemia. Both the incidence of mortality (HR = 3.36, 95% CI: 1.43-7.85, P = 0.001) and the incidence of mortality/readmission were significantly higher in patients with anemia (HR = 2.80, 95% CI: 2.03-3.86, P = 0.001). After adjusting for confounders, the association between anemia and mortality/readmission remained significant (P = 0.031). Almost one of three NSTEACS patients admitted to ICCU had anemia. Most patients underwent coronary angiography. Anemia was independently associated to poorer outcomes at 6 months

Estudio y valor pronóstico del estado de la microvasculatura coronaria en el síndrome de Takotsubo

La síndrome de Tako-Tsubo (STK) és una miocardiopatia aguda i transitòria, clàssicament considerada de bon pronòstic, i amb una ràpida recuperació de la funció ventricular. Tot i això, algunes sèries han reportat una morbimortalitat considerable en els pacients amb STK, fins i tot equiparable a la de les síndromes coronàries agudes (SCA). Tot i que l'etiopatogènia de l'STK no està completament definida, la toxicitat catecolaminèrgica i la disfunció microvascular coronària (CMD) han estat descrites com a dos dels principals mecanismes en aquesta entitat. Lestudi de l'estat de la microvasculatura coronària mitjançant paràmetres com l'índex de resistència microvascular (IMR) ha demostrat implicacions pronòstiques en pacients amb malaltia arterial coronària. Malgrat això, el seu ús en el dia a dia es troba limitat pels costos, la invasivitat i la necessitat d'usar un agent hiperèmic. Recentment s'ha validat un nou mètode no invasiu basat en la dinàmica de flux computacional (IMRangio) per a l'estudi de la funció microvascular coronària als SCA, fins i tot en condicions no hiperèmiques (NH-IMRangio). A través d'un compendi de publicacions, aquesta tesi doctoral descriu l'estat de les resistències microvasculars coronàries als pacients amb STK avaluades mitjançant el mètode NH-IMRangio, la seva associació amb les alteracions de la contractilitat ventricular esquerra i els biomarcadors cardíacs, així com la seva valor pronòstic en aquesta entitat. Al primer dels estudis publicats, es va avaluar l'estat de la microvasculatura coronària en els pacients amb STK mitjançant l'anàlisi del NH-IMRangio a les tres artèries coronàries epicàrdiques principals. Es va detectar una alta prevalença de CMD i una associació entre els valors de NH-IMRangio i els diferents patrons d'alteració de la contractilitat ventricular, així com amb el grau de disfunció ventricular i amb l'alliberament del pèptid NT-proBNP. Al segon dels estudis publicats, es van estudiar les implicacions pronòstiques del grau i l'extensió de la CMD avaluades mitjançant l'NH-IMRangio en els pacients amb STK. Es va observar que els pacients que presentaven valors més elevats de NH-IMRangio i aquells amb els tres territoris arterials coronaris amb un NH-IMRangio patològic, presentaven un pitjor pronòstic cardiovascular a l'any de seguiment.El síndrome de Tako-Tsubo (STK) es una miocardiopatía aguda y transitoria, clásicamente considerada de buen pronóstico, y con una rápida recuperación de la función ventricular. Sin embargo, algunas series han reportado una morbimortalidad considerable en los pacientes con STK, incluso equiparable a la de los síndromes coronarios agudos (SCA). A pesar de que la etiopatogenia del STK no está completamente definida, la toxicidad catecolaminérgica y la disfunción microvascular coronaria (CMD) han sido descritas como dos de los principales mecanismos en esta entidad. El estudio del estado de la microvasculatura coronaria mediante parámetros como el índice de resistencia microvascular (IMR) ha demostrado implicaciones pronósticas en pacientes con enfermedad arterial coronaria. A pesar de ello, su uso en el día a día se encuentra limitado por sus costes, su invasividad y por la necesidad de usar un agente hiperémico. Recientemente se ha validado un nuevo método no invasivo basado en la dinámica de flujo computacional (IMRangio) para el estudio de la función microvascular coronaria en los SCA, incluso en condiciones no hiperémicas (NH-IMRangio). A través de un compendio de publicaciones, esta tesis doctoral describe el estado de las resistencias microvasculares coronarias en los pacientes con STK evaluadas mediante el método NH-IMRangio, su asociación con las alteraciones de la contractilidad ventricular izquierda y los biomarcadores cardíacos, así como su valor pronóstico en esta entidad. En el primero de los estudios publicados, se evaluó el estado de la microvasculatura coronaria en los pacientes con STK mediante el análisis del NH-IMRangio en las tres arterias coronarias epicárdicas principales. Se detectó una alta prevalencia de CMD y una asociación entre los valores de NH-IMRangio y los diferentes patrones de alteración de la contractilidad ventricular, así como con el grado de disfunción ventricular y con la liberación del péptido NT-proBNP. En el segundo de los estudios publicados, se estudiaron las implicaciones pronósticas del grado y la extensión de la CMD evaluadas mediante el NH-IMRangio en los pacientes con STK. Se observó que los pacientes que presentaban valores más elevados de NH-IMRangio y aquéllos con los tres territorios arteriales coronarios con un NH-IMRangio patológico, presentaban un peor pronóstico cardiovascular al año.Takotsubo syndrome (TTS) is an acute and transient cardiomyopathy classically considered to have a good prognosis with rapid recovery of ventricular function. However, some series have reported considerable morbidity and mortality in patients with STK, comparable to that of acute coronary syndromes (ACS). Although the etiopathogenesis of STK is not completely defined, catecholaminergic toxicity and coronary microvascular dysfunction (CMD) have been described as two of the main mechanisms in this entity. The assessment of the status of the coronary microvasculature through parameters such as the microvascular resistance index (IMR) has shown prognostic implications in patients with coronary artery disease. However, it is not broadly used, due to its cost, invasiveness and the need for a hyperaemic agent. Recently, a novel angiography-derived index of microcirculatory resistance based on computational flow dynamics (IMRangio) has been validated for the study of coronary microvascular function in ACS, even in nonhyperemic conditions (NH-IMRangio). Through a compendium of publications, this doctoral thesis evaluates the status of the coronary microvascular resistances in TTS patients assessed by NH-IMRangio, its association with left ventricle wall motion abnormalities and cardiac biomarkers, as well as its prognostic value in patients with STK. In the first of the published studies, the status of the coronary microvasculature of patients with STK was measured by NH-IMRangio in the three main epicardial coronary arteries. A high incidence of CMD was detected in patients with STK. Moreover we found an association between the NH-IMRangio values and the different patterns of wall motion abnormalities, as well as with the degree of left ventricular dysfunction and with the release of NT-proBNP at admission. In the second of the published studies, we evaluated the prognostic implications of the degree and extent of CMD assessed by NH-IMRangio in patients with STK. We found that patients who presented higher NH-IMRangio values and those with 3 coronary artery territories with pathological NH-IMRangio values had a worse cardiovascular prognosis at one-year follow-up.Universitat Autònoma de Barcelona. Programa de Doctorat en Medicin

Estudio y valor pronóstico del estado de la microvasculatura coronaria en el síndrome de Takotsubo

La síndrome de Tako-Tsubo (STK) és una miocardiopatia aguda i transitòria, clàssicament considerada de bon pronòstic, i amb una ràpida recuperació de la funció ventricular. Tot i això, algunes sèries han reportat una morbimortalitat considerable en els pacients amb STK, fins i tot equiparable a la de les síndromes coronàries agudes (SCA). Tot i que l'etiopatogènia de l'STK no està completament definida, la toxicitat catecolaminèrgica i la disfunció microvascular coronària (CMD) han estat descrites com a dos dels principals mecanismes en aquesta entitat. Lestudi de l'estat de la microvasculatura coronària mitjançant paràmetres com l'índex de resistència microvascular (IMR) ha demostrat implicacions pronòstiques en pacients amb malaltia arterial coronària. Malgrat això, el seu ús en el dia a dia es troba limitat pels costos, la invasivitat i la necessitat d'usar un agent hiperèmic. Recentment s'ha validat un nou mètode no invasiu basat en la dinàmica de flux computacional (IMRangio) per a l'estudi de la funció microvascular coronària als SCA, fins i tot en condicions no hiperèmiques (NH-IMRangio). A través d'un compendi de publicacions, aquesta tesi doctoral descriu l'estat de les resistències microvasculars coronàries als pacients amb STK avaluades mitjançant el mètode NH-IMRangio, la seva associació amb les alteracions de la contractilitat ventricular esquerra i els biomarcadors cardíacs, així com la seva valor pronòstic en aquesta entitat. Al primer dels estudis publicats, es va avaluar l'estat de la microvasculatura coronària en els pacients amb STK mitjançant l'anàlisi del NH-IMRangio a les tres artèries coronàries epicàrdiques principals. Es va detectar una alta prevalença de CMD i una associació entre els valors de NH-IMRangio i els diferents patrons d'alteració de la contractilitat ventricular, així com amb el grau de disfunció ventricular i amb l'alliberament del pèptid NT-proBNP. Al segon dels estudis publicats, es van estudiar les implicacions pronòstiques del grau i l'extensió de la CMD avaluades mitjançant l'NH-IMRangio en els pacients amb STK. Es va observar que els pacients que presentaven valors més elevats de NH-IMRangio i aquells amb els tres territoris arterials coronaris amb un NH-IMRangio patològic, presentaven un pitjor pronòstic cardiovascular a l'any de seguiment.El síndrome de Tako-Tsubo (STK) es una miocardiopatía aguda y transitoria, clásicamente considerada de buen pronóstico, y con una rápida recuperación de la función ventricular. Sin embargo, algunas series han reportado una morbimortalidad considerable en los pacientes con STK, incluso equiparable a la de los síndromes coronarios agudos (SCA). A pesar de que la etiopatogenia del STK no está completamente definida, la toxicidad catecolaminérgica y la disfunción microvascular coronaria (CMD) han sido descritas como dos de los principales mecanismos en esta entidad. El estudio del estado de la microvasculatura coronaria mediante parámetros como el índice de resistencia microvascular (IMR) ha demostrado implicaciones pronósticas en pacientes con enfermedad arterial coronaria. A pesar de ello, su uso en el día a día se encuentra limitado por sus costes, su invasividad y por la necesidad de usar un agente hiperémico. Recientemente se ha validado un nuevo método no invasivo basado en la dinámica de flujo computacional (IMRangio) para el estudio de la función microvascular coronaria en los SCA, incluso en condiciones no hiperémicas (NH-IMRangio). A través de un compendio de publicaciones, esta tesis doctoral describe el estado de las resistencias microvasculares coronarias en los pacientes con STK evaluadas mediante el método NH-IMRangio, su asociación con las alteraciones de la contractilidad ventricular izquierda y los biomarcadores cardíacos, así como su valor pronóstico en esta entidad. En el primero de los estudios publicados, se evaluó el estado de la microvasculatura coronaria en los pacientes con STK mediante el análisis del NH-IMRangio en las tres arterias coronarias epicárdicas principales. Se detectó una alta prevalencia de CMD y una asociación entre los valores de NH-IMRangio y los diferentes patrones de alteración de la contractilidad ventricular, así como con el grado de disfunción ventricular y con la liberación del péptido NT-proBNP. En el segundo de los estudios publicados, se estudiaron las implicaciones pronósticas del grado y la extensión de la CMD evaluadas mediante el NH-IMRangio en los pacientes con STK. Se observó que los pacientes que presentaban valores más elevados de NH-IMRangio y aquéllos con los tres territorios arteriales coronarios con un NH-IMRangio patológico, presentaban un peor pronóstico cardiovascular al año.Takotsubo syndrome (TTS) is an acute and transient cardiomyopathy classically considered to have a good prognosis with rapid recovery of ventricular function. However, some series have reported considerable morbidity and mortality in patients with STK, comparable to that of acute coronary syndromes (ACS). Although the etiopathogenesis of STK is not completely defined, catecholaminergic toxicity and coronary microvascular dysfunction (CMD) have been described as two of the main mechanisms in this entity. The assessment of the status of the coronary microvasculature through parameters such as the microvascular resistance index (IMR) has shown prognostic implications in patients with coronary artery disease. However, it is not broadly used, due to its cost, invasiveness and the need for a hyperaemic agent. Recently, a novel angiography-derived index of microcirculatory resistance based on computational flow dynamics (IMRangio) has been validated for the study of coronary microvascular function in ACS, even in nonhyperemic conditions (NH-IMRangio). Through a compendium of publications, this doctoral thesis evaluates the status of the coronary microvascular resistances in TTS patients assessed by NH-IMRangio, its association with left ventricle wall motion abnormalities and cardiac biomarkers, as well as its prognostic value in patients with STK. In the first of the published studies, the status of the coronary microvasculature of patients with STK was measured by NH-IMRangio in the three main epicardial coronary arteries. A high incidence of CMD was detected in patients with STK. Moreover we found an association between the NH-IMRangio values and the different patterns of wall motion abnormalities, as well as with the degree of left ventricular dysfunction and with the release of NT-proBNP at admission. In the second of the published studies, we evaluated the prognostic implications of the degree and extent of CMD assessed by NH-IMRangio in patients with STK. We found that patients who presented higher NH-IMRangio values and those with 3 coronary artery territories with pathological NH-IMRangio values had a worse cardiovascular prognosis at one-year follow-up

Coronary microvascular dysfunction in takotsubo syndrome assessed by angiography-derived index of microcirculatory resistance: a pressure-wire-free tool

Background: Coronary microvascular dysfunction (CMD) has been proposed as a key mechanism in Takotsubo syndrome (TTS). The non-hyperaemic angiography-derived index of microcirculatory resistance (NH-IMRangio) has been validated as a pressure-wire-free tool for the assessment of coronary microvasculature. We aimed to study the presence of CMD in TTS patients and its association with levels of cardiac biomarkers and systolic dysfunction patterns. Methods: We recruited 181 consecutive patients admitted for TTS who underwent cardiac angiography at a tertiary center from January 2014 to January 2021. CMD was defined as an NH-IMRangio ≥ 25. Plasma levels of NT-proBNP, high-sensitive cardiac troponin T (hs-cTnT) and the left ventricular ejection fraction (LVEF) by echocardiography were measured at admission. Results: Mean age was 75.3 years, 83% were women and median LVEF was 45%. All patients presented CMD (NH-IMRangio ≥ 25) in at least one epicardial coronary artery. The left anterior descending artery (LAD) showed higher median NH-IMRangio values than left circumflex (LCx) and right coronary arteries (RCA) (44.6 vs. 31.3 vs. 36.1, respectively; p < 0.001). NH-IMRangio values differed among ventricular contractility patterns in the LAD and RCA (p = 0.0152 and 0.0189, respectively) with the highest values in the mid-ventricular + apical and mid-ventricular + basal patterns. NT-proBNP levels, but not high-sensitive cardiac troponin T (hs-cTnT), were correlated with both the degree and the extent of CMD in patients with TTS. Lower LVEF was also associated with higher NH-IMRangio values. Conclusions: CMD is highly prevalent in patients admitted for TTS and is associated with both a higher degree of systolic dysfunction and higher BNP levels, but not troponin

The Capacity of APOB-Depleted Plasma in Inducing ATP-Binding Cassette A1/G1-Mediated Macrophage Cholesterol Efflux—But Not Gut Microbial-Derived Metabolites—Is Independently Associated with Mortality in Patients with ST-Segment Elevation Myocardial Infarction

Impaired HDL-mediated macrophage cholesterol efflux and higher circulating concentrations of trimethylamine N-oxide (TMAO) levels are independent risk factors for cardiovascular mortality. The TMAO precursors, γ-butyrobetaine (γBB) and Trimethyllysine (TML), have also been recently associated with cardiovascular death, but their interactions with HDL-mediated cholesterol efflux remain unclear. We aimed to determine the associations between APOB depleted plasma-mediated macrophage cholesterol efflux and plasma TMAO, γBB, and TML concentrations and explore their association with two-year follow-up mortality in patients with acute ST-elevation myocardial infarction (STEMI) and unstable angina (UA). Baseline and ATP-binding cassette transporter ABCA1 and ABCG1 (ABCA1/G1)-mediated macrophage cholesterol efflux to APOB-depleted plasma was decreased in patients with STEMI, and the latter was further impaired in those who died during follow-up. Moreover, the circulating concentrations of TMAO, γBB, and TML were higher in the deceased STEMI patients when compared with the STEMI survivors or UA patients. However, after statistical adjustment, only ABCA1/G1-mediated macrophage cholesterol efflux remained significantly associated with mortality. Furthermore, neither the TMAO, γBB, nor TML levels altered the HDL-mediated macrophage cholesterol efflux in vitro. We conclude that impaired ABCA1/G1-mediated macrophage cholesterol efflux is independently associated with mortality at follow-up in STEMI patients