Safety and Tolerability of Sodium Thiosulfate in Patients with an Acute Coronary Syndrome Undergoing Coronary Angiography: A Dose-Escalation Safety Pilot Study (SAFE-ACS).

BACKGROUND: In animal studies, hydrogen sulfide (H2S) has been shown to protect the heart from ischemia-reperfusion injury. This study evaluates the safety and tolerability of the H2S donor sodium thiosulfate (STS) in patients with acute coronary syndrome (ACS). METHODS: Eighteen patients, undergoing coronary angiography for ACS, received STS intravenously immediately after arrival at the catheterization laboratory according to a "3 + 3 dose-escalation design" with fixed dosing endpoint (0, 2.5, 5, 10, 12.5, and 15 grams). This first dose STS was combined with verapamil and nitroglycerin required for transradial procedures. A second dose STS was administered 6 hours later. Primary endpoint was dose-limiting toxicity, defined as significant hemodynamic instability or death up to 24 hours or before discharge from the coronary care unit. Secondary outcomes included the occurrence of anaphylaxis, nausea, vomiting, and systolic blood pressure (SBP) course. RESULTS: Sixteen patients received two dosages of STS and two patients one dosage. None of the patients reached the primary endpoint, nor experienced a serious adverse event. We observed a clinically well-tolerated decline in SBP 1 hour after administration of the first STS dose and concomitant verapamil/nitroglycerin. SBP for all patients together reduced 16.8 (8.1-25.5) mmHg (P = 0.0008). No significant decline in SBP occurred after the second dose. Mild nausea was observed in one patient. CONCLUSION: This is the first report on sodium thiosulfate administration in patients with acute coronary syndromes. Our data suggest that sodium thiosulfate was well tolerated in this setting. The potential benefit of this intervention has to be examined in larger studies.

Agreement of 2D transthoracic echocardiography with cardiovascular magnetic resonance imaging after ST-elevation myocardial infarction.

BACKGROUND: This study was designed to investigate the agreement of 2D transthoracic echocardiography (2D TTE) with cardiovascular magnetic resonance imaging (CMR) in a contemporary population of ST-elevation myocardial infarction (STEMI) patients. METHODS: In this subanalysis of the GIPS-III trial, a randomized controlled trial investigating the administration of metformin in STEMI patients to prevent reperfusion injury, we studied 259 patients who underwent same-day CMR and 2D TTE assessments four months after hospitalization for a first STEMI. Bland-Altman analyses were performed to assess agreement between LV end-diastolic volume (LVEDV), LV end-systolic volume (LVESV), LV ejection fraction (LVEF), and LV mass measurements. Sensitivity and specificity of 2D TTE to detect categories of LVEF (≤35%, 35-50%, ≥50%) was determined. Linear regression of absolute differences in measurements between imaging modalities was used to investigate whether patient characteristics impact measurement bias. RESULTS: Pairwise difference (bias) and 95% limits of agreement between CMR and 2D TTE measurements were +84 (37, 147) ml for LVEDV, +39 (6, 85) ml for LVESV, -1.1 ± 13.5% for LVEF, and -75 (-154, -14) g for LV mass. Sensitivity and specificity of 2D TTE to detect subjects with moderately depressed LVEF (35-50%) as measured by CMR were 52% and 88% respectively. We observed a significant effect of enzymatic infarct size on bias between 2D TTE and CMR in measuring LVESV and LVEF (P = 0.029, P = 0.001 respectively), of age and sex on bias between 2D TTE and CMR in measuring LV mass (P = 0.027, P < 0.001) and LVEDV (P = 0.001, P = 0.039), and of heart rate on bias between 2D TTE and CMR in LV volume measurements (P = 0.004, P = 0.016). CONCLUSIONS: Wide limits of agreement, underestimation of LV volumes and overestimation of LV mass was observed when comparing 2D TTE to CMR. Enzymatic infarct size, age, sex, and heart rate are potential sources of bias between imaging modalities.

Time dependent apoptotic rates in the evolving coronary thrombus mass of myocardial infarction patients.

AIM: To study the rate of apoptotic cell death in the process of thrombus evolution after plaque rupture in myocardial infarction. METHODS: Paraffin embedded thrombosuction aspirates of 63 patients were stained with haematoxylin & eosin (H&E) to assess histologically the age of the thrombi: fresh (intact blood cells; <1day old), lytic (necrosis; 1-5days old) or organized (ingrowth of cells; >5days old). Presence of plaque constituents (atheroma including foam cells, cholesterol crystals calcifications and fibrous cap tissue) was also recorded. Immunohistochemical (double) stains with anti-caspase-3-antibody were used to visualize apoptosis and the cells involved. For the latter caspase-3 antibody was combined with cell-specific markers MPO (granulocytes), CD68 (macrophages), CD34 (endothelial cells), SMA-1 (smooth muscle cells) and a Feulgen stain (DNA). Second, the rate of apoptosis was evaluated in relation to the age of the thrombi. Platelet apoptosis was further evaluated with the use of TEM. RESULTS: From a total of 63 aspirates, plaque constituents were found in 33 of the aspirates, and in 15 of them lipid rich plaque tissue was the sole component. Age classification of all thrombus containing aspirates (n=48) resulted in 12 fresh (25%), 18 lytic (37.5%) and 18 organized (37.5%) thrombi. Apoptosis was more extensive in lytic thrombi than in fresh or organized thrombi (P<0.0001). Plaque-containing aspirates showed more apoptosis than aspirates without plaque (P<0.05). Immuno staining with caspase-3 antibody in combination with cell-specific markers showed that apoptosis was most extensive in MPO+ granulocytes. Caspase-3-positive platelets (CD61+ anucleate particles) were most abundant in lytic thrombi. Apoptosis in platelets was confirmed by ultrastructure. CONCLUSION: This study demonstrated a significant association between thrombus age and occurrence of apoptosis of granulocytes and also platelets, with highest rates in (fragile) lytic thrombi. We propose that apoptotic cell death in athero thrombosis could potentially serve as a biomarker for thrombus instability.