G-CSF for Extensive STEMI.

RATIONALE: In the exploratory Phase II STEM-AMI (Stem Cells Mobilization in Acute Myocardial Infarction) trial, we reported that early administration of G-CSF (granulocyte colony-stimulating factor), in patients with anterior ST-segment-elevation myocardial infarction and left ventricular (LV) dysfunction after successful percutaneous coronary intervention, had the potential to significantly attenuate LV adverse remodeling in the long-term. OBJECTIVE: The STEM-AMI OUTCOME CMR (Stem Cells Mobilization in Acute Myocardial Infarction Outcome Cardiac Magnetic Resonance) Substudy was adequately powered to evaluate, in a population showing LV ejection fraction ≤45% after percutaneous coronary intervention for extensive ST-segment-elevation myocardial infarction, the effects of early administration of G-CSF in terms of LV remodeling and function, infarct size assessed by late gadolinium enhancement, and myocardial strain. METHODS AND RESULTS: Within the Italian, multicenter, prospective, randomized, Phase III STEM-AMI OUTCOME trial, 161 ST-segment-elevation myocardial infarction patients were enrolled in the CMR Substudy and assigned to standard of care (SOC) plus G-CSF or SOC alone. In 119 patients (61 G-CSF and 58 SOC, respectively), CMR was available at baseline and 6-month follow-up. Paired imaging data were independently analyzed by 2 blinded experts in a core CMR lab. The 2 groups were similar for clinical characteristics, cardiovascular risk factors, and pharmacological treatment, except for a trend towards a larger infarct size and longer symptom-to-balloon time in G-CSF patients. ANCOVA showed that the improvement of LV ejection fraction from baseline to 6 months was 5.1% higher in G-CSF patients versus SOC (P=0.01); concurrently, there was a significant between-group difference of 6.7 mL/m2 in the change of indexed LV end-systolic volume in favor of G-CSF group (P=0.02). Indexed late gadolinium enhancement significantly decreased in G-CSF group only (P=0.04). Moreover, over time improvement of global longitudinal strain was 2.4% higher in G-CSF patients versus SOC (P=0.04). Global circumferential strain significantly improved in G-CSF group only (P=0.006). CONCLUSIONS: Early administration of G-CSF exerted a beneficial effect on top of SOC in patients with LV dysfunction after extensive ST-segment-elevation myocardial infarction in terms of global systolic function, adverse remodeling, scar size, and myocardial strain. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01969890.

Granulocyte-colony stimulating factor for large anterior ST-elevation myocardial infarction: rationale and design of the prospective randomized phase III STEM-AMI OUTCOME trial.

BACKGROUND: Granulocyte-colony stimulating factor (G-CSF) has been clinically tested in ST-elevation myocardial infarction (STEMI) with mixed results. Our 3-year follow-up data from STEM-AMI trial documented a sustained benefit of G-CSF on adverse ventricular remodeling after large anterior STEMI, when administered early and at a high-dose in patients with left ventricular (LV) dysfunction. The Aim of the present trial is to establish whether G-CSF improves hard clinical long-term outcomes. METHODS: The STEM-AMI OUTCOME is a prospective, multicenter, randomized, open-label, phase III trial. It will include 1,530 patients with anterior STEMI undergoing primary percutaneous coronary intervention 2 to 24 hours after symptoms onset and with LV ejection fraction ≤45% after successful reperfusion. Patients will be randomized 1:1 to G-CSF and/or standard treatment. The primary end point is a reduced occurrence of all-cause death, recurrence of myocardial infarction, or hospitalization due to heart failure in G-CSF-treated patients. Left ventricular remodeling will be assessed via cardiac ultrasound and a substudy with cardiac magnetic resonance will be carried out in 120 subjects. Accrual and follow-up periods will last 3 and 2 years, respectively. CONCLUSIONS: The STEM-AMI OUTCOME study is designed to be a rigorous controlled phase III trial with adequate statistical power to conclusively assess efficacy of G-CSF treatment in STEMI.

The hidden hypothesis: A disseminated tuberculosis case.

CASE PRESENTATION: 77-year-old former smoker admitted because of fatigue and abdominal distention. Past medical history positive for two previous hospitalizations for pericardial and pleural effusions (no diagnosis achieved). At admission erythrocyte sedimentation rate was 122mm per hour. Baseline investigations revealed ascitic, pleural and pericardial effusion. Effusions were tapped: neoplastic cells and acid-fast bacilli (AFB) were not identified, aerobic and mycobacterial culture resulted negative. QuantiFERON TB-Gold test was negative. Total body PET-CT and autoimmunity panel were negative. A neoplastic process was considered the most likely explanation. Before signing off the patient to comfort care, a reassessment was performed and an exposure to tuberculosis during childhood was documented. Because of constrictive pericarditis, pericardiectomy was performed: histologic examination showed chronic pericardial inflammation without granulomas, but Ziehl-Neelsen stain identified AFB and PCR was positive for Mycobacterium tuberculosis complex. Patient was started on anti-TB therapy with resolution of the effusions in the following months. Genes associated with defects in innate immunity were sequences and dentritic cells were studied, but no alterations were identified. DISCUSSION: A Bayesian approach to clinical decision making should be recommended. Interpretation of diagnostic tests should take into account the imperfect diagnostic performance of the majority of these tests. Further studies to investigate genetic susceptibility to tuberculosis are needed.

Effects of extracorporeal cardiopulmonary resuscitation on neurological and cardiac outcome after ischaemic refractory cardiac arrest.

BACKGROUND: Extracorporeal cardiopulmonary resuscitation is increasingly recognised as a rescue therapy for refractory cardiac arrest, nevertheless data are scanty about its effects on neurologic and cardiac outcome. The aim of this study is to compare clinical outcome in patients with cardiac arrest of ischaemic origin (i.e. critical coronary plaque during angiography) and return of spontaneous circulation during conventional cardiopulmonary resuscitation vs refractory cardiac arrest patients needing extracorporeal cardiopulmonary resuscitation. Moreover, we tried to identify predictors of survival after successful cardiopulmonary resuscitation. METHODS: We enrolled 148 patients with ischaemic cardiac arrest admitted to our hospital from 2011-2015. We compared clinical characteristics, cardiac arrest features, neurological and echocardiographic data obtained after return of spontaneous circulation (within 24 h, 15 days and six months). RESULTS: Patients in the extracorporeal cardiopulmonary resuscitation group ( n=63, 43%) were younger (59±9 vs 63±8 year-old, p=0.02) with lower incidence of atherosclerosis risk factors than those with conventional cardiopulmonary resuscitation. In the extracorporeal cardiopulmonary resuscitation group, left ventricular ejection fraction was lower than conventional cardiopulmonary resuscitation at early echocardiography (19±16% vs 37±11 p<0.01). Survivors in both groups showed similar left ventricular ejection fraction 15 days and 4-6 months after cardiac arrest (46±8% vs 49±10, 47±11% vs 45±13%, p not significant for both), despite a major extent and duration of cardiac ischaemia in extracorporeal cardiopulmonary resuscitation patients. At multivariate analysis, the total cardiac arrest time was the only independent predictor of survival. CONCLUSIONS: Extracorporeal cardiopulmonary resuscitation patients are younger and have less comorbidities than conventional cardiopulmonary resuscitation, but they have worse survival and lower early left ventricular ejection fraction. Survivors after extracorporeal cardiopulmonary resuscitation have a neurological outcome and recovery of heart function comparable to subjects with return of spontaneous circulation. Total cardiac arrest time is the only predictor of survival after cardiopulmonary resuscitation in both groups.

BM ageing: Implication for cell therapy with EPCs.

The bone marrow (BM) is a well-recognized source of stem/progenitor cells for cell therapy in cardiovascular diseases (CVDs). Preclinical and clinical studies suggest that endothelial progenitor cells (EPCs) contribute to reparative process of vascular endothelium and participate in angiogenesis. As for all organs and cells across the lifespan, BM and EPCs are negatively impacted by ageing due to microenvironment modifications and EPC progressive dysfunctions. The encouraging results in terms of neovascularization observed in young animals after EPC administration were mitigated in aged patients treated for ischemic CVDs. The limited efficacy of EPC-based therapy in clinical setting might be ascribed at least partly to ageing. In this review, we comprehensively discussed the age-related changes of BM and EPCs and their implication for cardiovascular cell-therapies. Finally, we examined alternative approaches under investigation to enhance EPC potency.

Tako-tsubo: a transitory impairment of microcirculation? A case report.

The tako-tsubo syndrome, or transient left ventricular apical ballooning, has been widely described in Japan as a cardiomyopathy which resembles acute myocardial infarction on presentation, but characterized by a normal coronary tree and a favorable outcome. Conversely few series have been described in Europe and etiology and mechanism are still unknown. We describe the case of a 74-year-old Italian woman with tako-tsubo cardiomyopathy, one of the first Italian cases reported to our knowledge. In the acute phase, echocardiography and ventriculography showed the typical mid-apical systolic left ventricular dysfunction, with an angiographically normal coronary tree. A few days after, technetium-99m single-photon emission computed tomography disclosed a large mid-apical perfusion defect and dobutamine stress echocardiography showed a typical "biphasic" response. Three months later, all of these tests normalized with normal left ventricular function. In conclusion, the results of functional tests, during the acute and subacute phases, suggest that, in the absence of evident coronary spasm, a transitory reduction of the coronary reserve played a role in the pathogenesis. In the absence of epicardial coronary obstruction this could be due to a transient microcircle dysfunction, and may be attributed to a spasm followed by impaired vasodilation capability.

G-CSF treatment for STEMI: final 3-year follow-up of the randomised placebo-controlled STEM-AMI trial.

OBJECTIVE: To assess whether granulocyte colony-stimulating factor (G-CSF) treatment induces a sustained benefit on adverse remodelling in patients with large anterior ST-elevation myocardial infarction (STEMI) and left ventricular (LV) dysfunction after successful reperfusion. METHODS: The STEM-AMI Trial was a prospective, placebo-controlled, multicentre study. Sixty consecutive patients with a first anterior STEMI, who underwent primary percutaneous coronary intervention 2-12 h after symptom onset, with LV ejection fraction (LVEF) ≤45% measured by echocardiography within 12 h after successful revascularisation (TIMI flow score ≥2), were randomised 1:1 to G-CSF (5 µg/Kg body weight b.i.d.) or placebo. Clinical events and Major Adverse Cardiac and Cerebrovascular Event (MACCE) were monitored, and LVEF, LV end-diastolic (LVEDV) and end-systolic (LVESV) volumes, and infarct size were evaluated by MRI at the final 3-year follow-up. RESULTS: Fifty-four patients completed the study, of whom 35 with MRI. No significant differences were found in mortality and MACCE between G-CSF and placebo-treated groups. The 3-year infarct size was not different between groups, whereas LVEDV was significantly lower in G-CSF (n=20) than in placebo (n=15) patients (170.1±8.1 vs 197.2±8.9 mL, respectively; p=0.033 at analysis of covariance). A significant inverse correlation was detected in G-CSF patients between the number of circulating CD34 cells at 30 days after reperfusion and the 3-year absolute and indexed LVEDV (ρ=-0.71, 95% CI -0.90 to -0.30, and ρ=-0.62, -0.86 to -0.14, respectively), or their change over time (r=-0.59, -0.85 to -0.11, and r=-0.55, -0.83 to -0.06, respectively). CONCLUSIONS: G-CSF therapy may be beneficial in attenuating ventricular remodelling subsequent to a large anterior STEMI in the long term. No differences have been detected in clinical outcome.

[From the coronary care unit to the intensive cardiac care unit: the evolution of the Cardiovascular Department of a tertiary center]. / Dalla unità di cura coronarica alla terapia intensiva cardiologica: l'evoluzione del Dipartimento Cardiovascolare dell'Ospedale di Lecco.

BACKGROUND: Substantial changes have occurred over time in the diagnoses, procedures and characteristics of patients admitted to coronary care units (CCU). Following the introduction of cardiac surgery activity in our hospital in December 2009, the aim of this study was to evaluate the changes in activity, processes of care and outcomes of patients consecutively admitted to our CCU after the reorganization of the Cardiovascular Department. METHODS: All 1674 consecutive patients admitted to the CCU from January 2009 to December 2010 were enrolled in this retrospective registry. RESULTS: In 2010, the number of patients referred from other hospitals or wards significantly increased (from 17.2% to 28.3%; p<0.001). Significant was also the increase of patients with ST-elevation myocardial infarction (n=190 to n=230, p<0.001), shock (n=20 to n=50, p<0.001), pulmonary edema (n=47 to n=64, p<0.05), cardiac arrest (n=2 to n=8, p<0.05), aortic dissection (n=0 to n=12; p<0.001). Conversely, the number of patients admitted for acute coronary syndromes without ST-segment elevation and GRACE risk score <140 significantly decreased (n=169 to n=52, p<0.001). In parallel, a significant increase in the use of intra-aortic balloon pump (2.0% to 5.6%, p<0.001), continuous hemofiltration (0.3% to 3.1%, p>0.001), non-invasive ventilation (5.6% to 10.5%, p<0.001) and mechanical ventilation (0% to 4.1%, p<0.001) was observed. Intensive care devices were more frequently used in the subgroups affected by shock, acute coronary syndromes without ST-segment elevation and GRACE risk score >200, and heart failure. Interestingly, despite the increase in high-risk clinical conditions the intra-CCU mortality did not change (3.1 vs 2.9%). CONCLUSIONS: Patients admitted to the CCU have high-risk acute clinical conditions. A model based on the sharing of cardiological, cardiac anesthesiological and surgical expertise is effective in increasing admission appropriateness and improving standards of care in a short period of time.

Granulocyte colony-stimulating factor attenuates left ventricular remodelling after acute anterior STEMI: results of the single-blind, randomized, placebo-controlled multicentre STem cEll Mobilization in Acute Myocardial Infarction (STEM-AMI) Trial.

AIMS: The aim of this study was to assess the effect of granulocyte colony-stimulating factor (G-CSF) on left ventricular (LV) function and volumes in patients with anterior ST-elevation myocardial infarction (STEMI) and depressed LV ejection fraction (EF). METHODS AND RESULTS: Sixty consecutive patients with anterior STEMI, undergoing primary angioplasty percutaneous coronary intervention (PCI), with symptom-to-reperfusion time of 2-12 h and EF ≤45% after PCI, were randomized to G-CSF 5 µg/kg b.i.d. subcutaneously (n = 24) or placebo (n = 25) for 5 days, starting <12 h after PCI. The primary endpoint was an increase from baseline to 6 months of 5% in left ventricular ejection fraction (LVEF), as measured by magnetic resonance imaging (MRI). Co-primary endpoint was a ≥20 mL difference in end-diastolic volume (EDV). Infarct size and perfusion were evaluated with late gadolinium enhancement (LGE) and gated (99m)Technetium Sestamibi single-photon emission computed tomography (SPECT). Left ventricular EDV and end-systolic volume (ESV) increased from baseline to 6 months in the placebo group (81.7 ± 24.4 to 94.4 ± 26.0 mL/m(2), P < 0.00005 and 45.2 ± 20.0 to 53.2 ± 23.8 mL/m(2), P = 0.016) but were unchanged in the G-CSF group (82.2 ± 20.3 to 85.7 ± 23.7 mL/m(2), P = 0.40 and 46.0 ± 18.2 to 48.4 ± 20.8 mL/m(2), P = 0.338). There were no significant differences in EF or perfusion between groups. A significant reduction in transmural LGE segments was seen at 6 months in the G-CSF vs. placebo groups (4.38 ± 2.9 to 3.3 ± 2.6, P = 0.04 and 4.2 ± 2.6 to 3.6 ± 2.7, P = 0.301, respectively). Significantly more placebo patients had a change in left ventricular end-diastolic volume abovethe median (9.3 mL/m(2)) when reperfusion time exceeded 180 min (median time-to-reperfusion) (P = 0.0123). Severe adverse events were similar between groups. CONCLUSION: Early G-CSF administration attenuates ventricular remodelling in patients with anterior STEMI and EF ≤45% after successful PCI.

Capecitabine-induced cardiotoxicity: when to suspect? How to manage? A case report.

We present a case of capecitabine-induced cardiac toxicity manifested by chest pain, ST-segment elevation and ventricular tachycardia. Symptoms and ECG alterations were completely reversible after withdrawal of the drug. Coronary angiography demonstrated the absence of epicardial coronary spasm. We suggest cardiac monitoring with ECG Holter and effort ECG during the first days of drug administration. Prompt evaluation of chest pain in this setting is of paramount importance.

Cardiac arrhythmias due to severe hypokalemia in a patient with classic Bartter disease.

We report a young girl with classic Bartter disease (type III) with severe hypokalemia (< or = 2.0 mmol/l) who developed a prolonged heart rate-corrected QT interval of 510 ms (upper reference 430 ms) and ST segment depression in all leads. Holter electrocardiography was performed (with a plasma potassium level of 2.0 mmol/l) and it disclosed a stable sinus rhythm, a prolonged correct QT interval, more-evident ST segment depression during an increase in heart rate, a few single premature ventricular complexes, and nocturnal conduction abnormalities such as second-degree atrioventricular block 2:1. In the light of these results, the treatment was modified by increasing indomethacin from 1.5 to 3 mg/kg per day and adding spironolactone at a dose of 5 mg/kg per day. After 10 days, plasma potassium levels increased to 2.7 mmol/l and electrocardiographic abnormalities regressed. No other cardiac abnormalities were noted when the serum potassium was maintained > 2.5 mmol/l. In conclusion, this case report supports the link between arrhythmic events and chronic renal hypokalemic alkalosis in renal tubular disorders. We highlight the importance of standardizing the use of rest electrocardiography and 24-h Holter monitoring to diagnose arrhythmic events in children with severe hypokalemic renal disorders, especially in those with a plasma potassium < 2.5 mmol/l. The importance of beginning early medical treatment, to improve plasma potassium levels and reverse cardiac abnormalities, is emphasized.