caldaret and Myocardial-Infarction

Primary percutaneous coronary intervention (PCI) decreases myocardial damage in patients with ST-elevation myocardial infarction (STEMI). Cellular reperfusion injury associated with calcium overload may limit myocardial salvage. We previously showed (CASTEMI trial) that caldaret (MCC-135), which modulates myocardial calcium handling when administered before PCI in patients with STEMI, did not change residual left ventricular (LV) function. The aim of this subanalysis was to examine whether caldaret decreases the incidence of LV dysfunction (LV ejection fraction

Topics: Angioplasty, Balloon, Coronary; Benzenesulfonates; Dose-Response Relationship, Drug; Electrocardiography; Female; Follow-Up Studies; Heart Ventricles; Humans; Incidence; Injections, Intravenous; Male; Middle Aged; Myocardial Infarction; Piperazines; Stroke Volume; Tomography, Emission-Computed, Single-Photon; Treatment Outcome; Ventricular Dysfunction, Left

We sought to determine the best cardiac biomarker to predict infarct size, left ventricular ejection fraction (LVEF), and clinical outcome in patients undergoing primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI).. The cardiac biomarkers, creatine kinase (CK), CK-MB, and troponins T and I are routinely measured after myocardial infarction. However, their correlation with functional and clinical outcomes after PCI for STEMI is not well established.. In the EVOLVE (EValuation Of MCC-135 for Left VEntricular Salvage in Acute Myocardial Infarction) trial, patients were randomized to receive intracellular calcium modulator as adjunct to primary PCI for first large STEMI. Cardiac biomarker levels were determined in 378 patients before PCI and serially up to 72 h. Single-photon emission computed tomography was performed after 5 and 30 days, and patients were monitored up to 180 days.. All single time-point, peak, and area under time-concentration curve of CK, CK-MB, and troponins T and I after PCI significantly correlated with infarct size and LVEF. In particular, 72-h troponin I (TnI72h) correlated strongly with 5-day and 30-day infarct size (r > 0.70; p < 0.001). A TnI72h threshold >55 ng/ml was 90% sensitive for large infarct size (> or =10%) and low LVEF (< or =40%) with specificities of 70% and 52%, respectively (c = 0.88, 0.81; p < 0.001). The highest TnI72h tertile was associated with increased 180-day composite clinical events (23% vs. 23% vs. 42%; p = 0.001) and independently predicted adverse events (hazard ratio = 2.3; p = 0.01).. Assessing TnI72h after primary PCI is a simple, effective method to estimate infarct size, LVEF, and potentially useful for risk stratification.

Topics: Aged; Angioplasty, Balloon, Coronary; Benzenesulfonates; Biomarkers; Cardiovascular Agents; Coronary Angiography; Creatine Kinase, MB Form; Disease-Free Survival; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Myocardial Infarction; Myocardium; Piperazines; Predictive Value of Tests; Proportional Hazards Models; Prospective Studies; Risk Assessment; Stroke Volume; Time Factors; Tomography, Emission-Computed, Single-Photon; Treatment Outcome; Troponin I; Troponin T; United States; Ventricular Function, Left

The objective of the study was to test the hypothesis that intracellular calcium modulation by 5-methyl-2-[piperazin-1-yl] benzene sulfonic acid monohydrate (MCC-135 [Caldaret]; Mitsubishi Pharma Corporation, Osaka, Japan) would preserve left ventricular function and reduce infarct size in patients undergoing primary percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI).. Calcium overload inside myocytes during ischemia and reperfusion not only affects myocardial function but also may be related to myocyte necrosis. MCC-135 is the first in a new class of agents that modulate intracellular calcium overload.. Patients with acute STEMI undergoing primary PCI were randomized into placebo, low-dose, and high-dose MCC-135 groups. The predefined target population was those with anterior myocardial infarction and pre-PCI TIMI grade flow 0 or 1. Left ventricular ejection fraction (LVEF) on Day 5 was the primary end point. Secondary end points included infarct size measured by single photon emission computed tomography and by serum cardiac markers. Patients were followed up to 30 days for clinical outcome.. Among 500 patients enrolled, 141 qualified as the target population. In this target population, there was no difference in the LVEF between 3 groups (placebo: 47.0% +/- 1.7% [mean +/- SEM], the low dose: 47.4% +/- 1.7%, the high dose: 45.1% +/- 2.0%). The infarct size on day 5 was not significantly different between the groups. The composite clinical outcome occurred in 25.5% in the placebo group, in 19.2% in the low-dose group, and in 34.2% in the high-dose group during a 30-day follow-up period (P = nonsignificant). MCC-135 appeared to be safe and well tolerated.. There were no significant benefits of MCC-135 on preservation of LVEF and reduction of infarct size on day 5 in patients with STEMI undergoing primary PCI.

Topics: Aged; Angioplasty, Balloon, Coronary; Benzenesulfonates; Cardiac Catheterization; Combined Modality Therapy; Coronary Angiography; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Electrocardiography; Female; Follow-Up Studies; Humans; Infusions, Intravenous; Male; Middle Aged; Myocardial Infarction; Piperazines; Probability; Reference Values; Risk Assessment; Salvage Therapy; Stroke Volume; Survival Rate; Treatment Outcome; Ventricular Function, Left

To examine the safety and efficacy of intravenous caldaret in patients with large acute ST-elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI).. STEMI patients (n=387) with > or =10 mm summed ST-deviation on electrocardiogram were randomized to receive a 48 h infusion of caldaret 57.5 mg [lower dose (LD)], caldaret 172.5 mg [higher dose (HD)], or placebo, starting before PCI. Both HD and LD were well tolerated. In 247 patients with pre-PCI TIMI 0/1, there was no effect of HD or LD on single photon emission computed tomography infarct size or ejection fraction assessed at Day 7 and Day 30. Subgroup analyses suggest that future work in patients with anterior MI might be warranted.. This first human experience with caldaret prior to direct PCI for large STEMI shows a good safety profile. No evidence of efficacy was discerned. Subgroup analyses in anterior MI patients showed some effects in endpoints studied, however, these findings require confirmation in a further study if a drug effect is to be established.

Topics: Angioplasty, Balloon, Coronary; Benzenesulfonates; Cardiotonic Agents; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Myocardial Infarction; Piperazines; Treatment Outcome

As a consequence of acute ischemia and reperfusion in patients with acute ST elevation myocardial infarction, calcium overload inside myocytes not only affects myocardial contraction, relaxation, and myocyte recovery following reperfusion, but also may be related to myocyte necrosis and fatal arrhythmia. MCC-135 is the first in a new class of agents that reduce intracellular calcium overload. Pre-clinical and early clinical studies yielded promising results for patients with ST elevation myocardial infarction. The Evaluation of MCC-135 for Left Ventricular Salvage in Acute MI (EVOLVE) study is a Phase 2a, multicenter, randomized, double-blind, placebo-controlled clinical trial of 2 new doses of MCC-135 (4.5 mg/kg/48 hours and 9.0 mg/kg/48 hours) as adjunct therapy for preservation of left ventricular function and reduction of infarct size in patients undergoing primary percutaneous coronary intervention (PCI) for electrocardiographically moderate-large ST elevation myocardial infarction. The primary endpoint will be left ventricular ejection fraction on Day 5 post myocardial infarction as determined by single photon emission computed tomography (SPECT). Secondary endpoints will include SPECT and echocardiographic assessments, serum cardiac markers, clinical outcomes, and safety measures at specific time points through Day 30 post myocardial infarction. Follow-up clinical and safety assessments will be continued until Day 180. The rationale, design, and methods of the EVOLVE study are described in this paper, along with 2 sub-studies, involving a comparison of pre- and post-PCI measurements with either SPECT or echocardiography, to examine myocardial salvage and the time course of changes in myocardial infarction size and left ventricular function. MINIABSTRACT: The Evaluation of MCC-135 for Left Ventricular Salvage in Acute MI (EVOLVE) study is a Phase 2, multicenter, randomized, double-blind, placebo-controlled clinical trial of two doses of MCC-135, first in a new class of agents that reduce intracellular calcium overload, as adjunct therapy for preservation of left ventricular function and reduction of infarct size in patients with moderate-large STEMI undergoing primary PCI. The rationale, design, and methods of the EVOLVE study, along with two sub-studies, are described in this paper.

Topics: Acute Disease; Adolescent; Adult; Angioplasty, Balloon, Coronary; Benzenesulfonates; Calcium; Double-Blind Method; Echocardiography; Humans; Male; Middle Aged; Muscle Cells; Myocardial Infarction; Myocardial Reperfusion Injury; Necrosis; Piperazines; Radiography; Tomography, Emission-Computed, Single-Photon; Ventricular Function, Left

The cardioprotective effect of caldaret, a novel intracellular Ca(2+) handling modulator that acts through reverse-mode Na(+)/Ca(2+) exchanger inhibition and potential sarcoplasmic reticulum (SR) Ca(2+) uptake enhancement, against reperfusion injury was investigated. We employed a canine model of myocardial infarction induced by 90-min occlusion of left circumflex (LCX) coronary artery followed by 4 h of reperfusion. Intravenously infused caldaret (3 or 30 microg/kg per hour) for 30 min at LCX-reperfusion markedly reduced infarct size (by 51.3% or 71.9%, respectively). This cardioprotection was accompanied by an acceleration of left ventricular (LV) contraction and relaxation during reperfusion, but not by an increase in ischemic regional transmural myocardial blood flow (TMBF) or endocardial/epicardial blood flow ratio (Endo/Epi ratio) or a reduction in double-product throughout the protocol. Diltiazem (2000 microg/kg per hour) also reduced infarct size (by 36.1%), but unlike caldaret, was accompanied by the significant increase in Endo/Epi ratio in the ischemic region and decrease in double-product. There were significant inverse relationships between infarct size and ischemic regional TMBF in all groups. Caldaret, but not diltiazem shifted the regression line downward with a flatter slope. These results suggest that the amelioration of intracellular Ca(2+) handling dysfunction achieved by caldaret leads to cardioprotective effects against reperfusion injury following prolonged ischemia.

Topics: Algorithms; Animals; Benzenesulfonates; Blood Pressure; Calcium; Calcium Channel Blockers; Coronary Circulation; Diltiazem; Dogs; Heart; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Piperazines; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Sodium-Calcium Exchanger