Functional Significance in Spontaneous Recanalization of a Coronary Thrombus.

Spontaneous recanalization of a coronary thrombus is an uncommon finding that may be confounded without intravascular imaging. There is little evidence regarding the functional impact of these lesions, which may be relevant to proper management. We present two cases of recanalized thrombus in which functional testing guided appropriate management.

Colchicine in acute heart failure: Rationale and design of a randomized double-blind placebo-controlled trial (COLICA).

AIMS: Heart failure (HF) elicits a pro-inflammatory state, which is associated with impaired clinical outcomes, but no anti-inflammatory therapies have demonstrated a clinical benefit yet. Inflammatory pathways related with the interleukin-1 axis are overactivated during episodes of acute HF. Colchicine, an anti-inflammatory drug with proven benefits in acute pericarditis and ischaemic heart disease, may target this inflammatory response. This study aims to assess the efficacy of colchicine in acute HF patients. METHODS: COLICA is a multicentre, randomized, double-blind, placebo-controlled trial enrolling 278 patients across 12 sites. Patients presenting with acute HF, clinical evidence of congestion requiring ≥40 mg of intravenous furosemide and N-terminal pro-B-type natriuretic peptide (NT-proBNP) >900 pg/ml, are eligible for participation. Patients are enrolled irrespective of left ventricular ejection fraction, HF type (new-onset or not) and setting (hospital or outpatient clinic). Patients are randomized 1:1 within the first 24 h of presentation to either placebo or colchicine, with an initial loading dose of 2 mg followed by 0.5 mg every 12 h for 8 weeks (reduced dose if <70 kg, >75 years old, or glomerular filtration rate <50 ml/min/1.73 m2). The primary efficacy endpoint is the time-averaged proportional change in NT-proBNP concentrations from baseline to week 8. Key secondary and exploratory outcomes include symptoms, diuretic use, worsening HF episodes, related biomarkers of cardiac stress and inflammation, total and cardiovascular readmissions, mortality and safety events. CONCLUSION: COLICA will be the first randomized trial testing the efficacy and safety of colchicine for acute HF.

Withdrawal of drug therapy in responders to cardiac resynchronization therapy: rationale and design of the REMOVE trial.

INTRODUCTION AND OBJECTIVES: Cardiac resynchronization therapy (CRT) is an effective treatment for patients with nonischemic dilated cardiomyopathy associated with left bundle branch block (LBBB). In these patients, the device can normalize left ventricular ejection fraction (LVEF). Nevertheless, it remains unclear whether CRT responders still require neurohormonal blockers. The aim of this study is to determine the long-term safety of withdrawing drug therapy in these patients. METHODS: The REMOVE trial is a prospective, multicenter, open-label and randomized 1:1 study designed to assess the effect of withdrawing neurohormonal blockers in patients with nonischemic dilated cardiomyopathy associated with left bundle branch block who recovered LVEF after CRT. The study will include a 12-month follow-up with the option to continue into the follow-up extension phase for up to 24 months. The primary endpoint is the recurrence of cardiomyopathy defined as any of the following criteria: a) a reduction in LVEF >10% (provided the LVEF is <50%); b) a reduction in LVEF >10% accompanied by an increase >15% in the indexed end-systolic volume relative to the previous value and in a range higher than the normal values, or c) decompensated heart failure requiring intravenous diuretic administration. In patients meeting the primary endpoint, drug therapy will be restarted. CONCLUSIONS: The results of this study will help to enhance our understanding of CRT superresponders, a specific group of patients. Registred at ClinicalTrials.gov (Identifier: NCT05151861).

Factor de transcripción TBX1 en el remodelado cardiaco asociado al infarto de miocardio / The TBX1 transcription factor in cardiac remodeling after myocardial infarction

Introducción y objetivos: TBX1 es un factor de transcripción importante en el desarrollo embrionario del corazón. Se desconoce su implicación en el remodelado miocárdico tras infarto agudo de miocardio (IAM) y si es modulable por una terapia con beneficio demostrado como es el bloqueo del receptor mineralocorticoideo. Métodos: Se sometió a IAM a 60 ratas mediante ligadura de la coronaria izquierda: 50 animales fueron aleatorizados a ser sacrificados pasadas 1, 2, 4, 12 o 24 semanas; 10 animales se trataron con eplerenona (100 mg/kg/día) 7 días antes del IAM, hasta su sacrificio (4 semanas después); 8 animales se sometieron a cirugía sin ligadura (control). Se analizó la expresión cardiaca de TBX1, genes fetales y marcadores de fibrosis. Resultados: La expresión génica y proteica de TBX1 se incrementó en el miocardio infartado, con pico de expresión 1 semana tras el IAM (p < 0,01), sin variar en el miocardio no infartado. Los genes fetales y los marcadores de fibrosis también aumentaron, con expresión máxima 4 semanas (p < 0,001) y 1 semana (p < 0,01) tras el IAM respectivamente. La expresión de TBX1 se correlacionó con la de los marcadores de fibrosis (p < 0,01), pero no con los genes fetales. La eplerenona redujo el incremento de TBX1 y la fibrosis inducida tras IAM, que se asociaron con una mejora de función y remodelado ventricular por ecocardiografía. Conclusiones: Estos resultados muestran la reactivación de la expresión de TBX1 e indican su implicación en la fibrosis y el remodelado cardiacos tras el IAM y que puede participar en el beneficio del bloqueo mineralocorticoideo (AU)

Introduction and objectives: The transcription factor TBX1 plays an important role in the embryonic development of the heart. Nothing is known about its involvement in myocardial remodeling after acute myocardial infarction (AMI) and whether its expression can be modulated by a treatment with proven benefit such as mineralocorticoid receptor blockade. Methods: Acute myocardial infarction was induced in 60 rats via left coronary artery ligation: 50 animals were randomized to be euthanized after 1, 2, 4, 12, or 24 weeks; 10 animals were treated with eplerenone (100 mg/kg/days) 7 days before the AMI until their euthanasia (4 weeks later); 8 additional animals underwent surgery without ligation (control). We analyzed the cardiac expression of TBX1, fetal genes, and fibrosis markers. Results: The gene and protein expression of TBX1 was increased in the infarcted myocardium, peaking 1 week after AMI (P < .01), without changes in the non-infarcted myocardium. Levels of the fetal genes and fibrosis markers also increased, peaking 4 weeks (P < .001) and 1 week (P < .01) after AMI, respectively. The TBX1 expression was correlated with that of the fibrosis markers (P < .01) but not the fetal genes. Eplerenone reduced the TBX1 increase and fibrosis induced by AMI, with an association improvement in ventricular function and remodeling in echocardiography. Conclusions: These results show the reactivated expression of TBX1 and indicate its involvement in cardiac fibrosis and remodeling after AMI and its participation in the benefit from mineralocorticoid receptor blockade (AU)

The TBX1 Transcription Factor in Cardiac Remodeling After Myocardial Infarction.

INTRODUCTION AND OBJECTIVES: The transcription factor TBX1 plays an important role in the embryonic development of the heart. Nothing is known about its involvement in myocardial remodeling after acute myocardial infarction (AMI) and whether its expression can be modulated by a treatment with proven benefit such as mineralocorticoid receptor blockade. METHODS: Acute myocardial infarction was induced in 60 rats via left coronary artery ligation: 50 animals were randomized to be euthanized after 1, 2, 4, 12, or 24 weeks; 10 animals were treated with eplerenone (100 mg/kg/days) 7 days before the AMI until their euthanasia (4 weeks later); 8 additional animals underwent surgery without ligation (control). We analyzed the cardiac expression of TBX1, fetal genes, and fibrosis markers. RESULTS: The gene and protein expression of TBX1 was increased in the infarcted myocardium, peaking 1 week after AMI (P < .01), without changes in the noninfarcted myocardium. Levels of the fetal genes and fibrosis markers also increased, peaking 4 weeks (P < .001) and 1 week (P < .01) after AMI, respectively. The TBX1 expression was correlated with that of the fibrosis markers (P < .01) but not the fetal genes. Eplerenone reduced the TBX1 increase and fibrosis induced by AMI, with an association improvement in ventricular function and remodeling in echocardiography. CONCLUSIONS: These results show the reactivated expression of TBX1 and indicate its involvement in cardiac fibrosis and remodeling after AMI and its participation in the benefit from mineralocorticoid receptor blockade.

Clinical relevance of sST2 in cardiac diseases.

ST2 has two main isoforms, ST2L and soluble isoform of ST2 (sST2), by alternative splicing. The interaction between interleukin (IL)-33 and the transmembrane isoform ST2L is up-regulated in response to myocardial stress and exerts cardio-protective actions in the myocardium by reducing fibrosis, hypertrophy and enhancing survival. The circulating isoform sST2, by sequestering IL-33, abrogates these favorable actions and will be elevated as a maladaptive response to cardiac diseases. Indeed, circulating sST2 concentrations correlate with a worse phenotype of disease including adverse remodeling and fibrosis, cardiac dysfunction, impaired hemodynamics and higher risk of progression. In patients with acute and chronic heart failure, sST2 concentrations are strongly predictive of death, regardless of the cause and left ventricle (LV) ejection fraction, and contribute relevant information in addition to other prognosticators and biomarkers, as natriuretic peptides or troponins. sST2 also retains prognostic information in the setting of acute myocardial infarction (AMI) and predicts cardiovascular death and risk of heart failure (HF) development in these patients. sST2 could also be a promising tool to stratify the risk of sudden cardiac death (SCD) in patients with depressed LV ejection fraction. Therefore, sST2 represents a clinically relevant biomarker reflecting pathophysiological processes and contributing predictive information in the setting of several cardiovascular diseases, and especially in patients with HF.

Prognostic Value and Kinetics of Soluble Neprilysin in Acute Heart Failure: A Pilot Study.

OBJECTIVES: This study sought to examine the prognostic value of the soluble form of neprilysin (sNEP) in acute heart failure (AHF) and sNEP kinetics during hospital admission. BACKGROUND: sNEP was recently identified in chronic heart failure (HF) and was associated with cardiovascular outcomes. METHODS: A total of 350 patients (53% women, mean 72.6 ± 10.7 years of age) were included in the study. Primary endpoints were composites of cardiovascular death or HF hospitalizations at short-term (2 months) and long-term (mean: 1.8 ± 1.2 years) follow-up. sNEP was measured using an ad hoc-modified enzyme-linked immunosorbent assay, and its prognostic value was assessed using Cox regression analyses. In a subgroup of patients, sNEP was measured both at admission and at discharge (n = 92). RESULTS: Median admission sNEP concentrations were 0.67 ng/ml (Q1 to Q3: 0.37 to 1.29), and sNEP was significantly associated, in age-adjusted Cox regression analyses, with the composite endpoint at short-term (hazard ratio [HR]: 1.29; 95% confidence interval [CI]: 1.04 to 1.61; p = 0.02) and long-term (HR: 1.23; 95% CI: 1.01 to 1.05; p = 0.003) follow-up. In multivariate Cox analyses that included clinical variables and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) concentration, sNEP concentration at admission showed a clear trend toward significance for the composite endpoint at 2 months (HR: 1.22; 95% CI: 0.97 to 1.53; p = 0.09) and remained significant at the end of follow-up (HR: 1.21; 95% CI: 1.04 to 1.40; p = 0.01). At discharge, sNEP levels decreased from 0.70 to 0.52 ng/ml (p = 0.06). CONCLUSIONS: Admission sNEP concentration was associated with short- and long-term outcomes in AHF, and dynamic sNEP concentrations were observed during hospital admission. These preliminary data may be hypothesis-generating for the use of NEP inhibitors in AHF.