Thrombus and Inflammation Study in Sudden Cardiac DEath
Condition: Sudden Cardiac Death; Acute Myocardial Infarction
MeSH terms: Myocardial Infarction; Death, Sudden, Cardiac; Inflammation; Infarction; Death
Study type: Interventional

Summary: 
      Sudden death is a natural death occurring within one hour after the onset of symptoms. It
      remains a major public health problem and accounts for 5 to 10 % of the annual total
      mortality ie about 300.000 in the United States. Despite community-based interventions,
      overall survival remains below 5%. Better understanding of the mechanisms causing sudden
      death could allow early identification of high risk subjects and implementation of specific
      prevention strategies. The cause of more than 90% of sudden deaths is cardiac with
      ventricular fibrillation or fast ventricular tachycardia complicating an underlying heart
      disease. Coronary heart disease and its consequences account for at least 80% of sudden
      cardiac deaths. Several risk factors associated with sudden death and not with myocardial
      infarction have been identified in population-based studies. However, the relationship
      between the occurrence of a coronary artery occlusion and the onset of arrhythmia is unclear.
      In particular, coronary artery occlusion can be rapidly followed by chest pain, which acts as
      a signal and allows identification of patients for emergency reperfusion. However, in some
      cases, the coronary artery occlusion is followed by a sudden onset of arrhythmia and sudden
      death. Recent data suggest that acute coronary occlusion is caused by plaque erosion or
      rupture and is followed by an intense local inflammation and rapid thrombus formation. Our
      hypothesis is that the speed of thrombus formation and coronary occlusion determines the
      clinical symptoms. Slow and progressive thrombus formation is likely to induce myocardial
      pre-conditioning thereby reducing the occurrence of ventricular arrhythmia. In contrast,
      rapid thrombus formation followed by acute coronary artery occlusion and ischemia is more
      likely to trigger fatal ventricular arrhythmia. During angioplasty procedures, coronary
      artery thrombus are aspirated, providing the opportunity for pathological studies. The aim of
      the TIDE study (Thrombus and Inflammation in Sudden Death) is therefore to compare the
      composition and age of thrombus collected at the site of coronary occlusion in patients with
      sudden death due to acute coronary artery occlusion and patients with an acute myocardial
      infarction without ventricular arrhythmia. The following hypothesis will be tested : fresh
      thrombus is more frequent in patients with sudden cardiac death versus patients with acute
      myocardial infarction without ventricular arrhythmia.
    

Detailed description: 
      Sudden death is a natural death occurring within one hour after the onset of symptoms. It
      remains a major public health problem and accounts for 5 to 10 % of the annual total
      mortality ie about 40 000 deaths in France and 300.000 in the United States.(1) Despite
      community-based interventions, overall survival remains below 5%. (2) Better understanding of
      the mechanisms causing sudden death could allow early identification of high risk subjects
      and implementation of specific prevention strategies. (3)The cause of more than 90% of sudden
      deaths is cardiac with ventricular fibrillation or fast ventricular tachycardia complicating
      an underlying heart disease. (4) Coronary heart disease and its consequences account for at
      least 80% of sudden cardiac deaths and hypertrophic and dilated cardiomyopathies account for
      another 10 to 15% of cardiac causes.(4,5) Several risk factors associated with sudden death
      and not with myocardial infarction have been identified in population-based studies.(6-10)
      However, the relationship between the occurrence of a coronary artery occlusion and the onset
      of arrhythmia is unclear.The Framingham study reported that sudden death occurred without
      prior manifestations of coronary heart disease in more than 50% of men and 65% of women. (11)
      Data from 10 countries from WHO MONICA PROJECT show that sudden deaths are more frequent than
      non sudden coronary deaths until age 60. (figure). In a study on the value of immediate
      coronary angiography and angioplasty in survivors of SCD, a recent coronary artery occlusion
      was found in over 50% of patients and unstable coronary artery lesions in 20% (12). In two
      series based on autopsies, the rate of coronary artery lesions in non-survivors of SCD was
      over 80% (13-15). In a study based on autopsies of non-survivors of SCD, fresh thrombus was
      found in a majority of cases. (2)Furthermore, noninflammatory plaque erosion was found as an
      underlying cause to thrombus formation in 40% of cases (14). In this case, thrombus is formed
      on a denuded endothelial plaque surface and is in direct contact with activated smooth muscle
      cells. In 211 patients with non-complicated acute myocardial infarction caused by acute
      coronary occlusion, SASKIA et al studied the age of intracoronary thrombi, aspirated during
      angioplasty (16). In at least 50% of patients, thrombi were days or weeks old, thereby
      suggesting ischemic pre-conditioning in this sub-group of acute myocardial infarction
      patients with no ventricular arrhythmia. Maier et al studied intra-coronary concentrations of
      selected inflammatory biomarkers in 42 patients with acute myocardial infarction (17). High
      levels of interleukin 6 and serum amyloid A were found at the occlusion site; and these
      levels were even higher in patients with no previous clinical symptoms before the acute
      myocardial infarction. These data suggest that plaque erosion or rupture is followed by an
      intense local inflammation and rapid thrombus formation. Our hypothesis is that the speed of
      thrombus formation and coronary occlusion determines the clinical symptoms. Slow and
      progressive thrombus formation is likely to induce myocardial pre-conditioning thereby
      reducing the occurrence of ventricular arrhythmia. In contrast, rapid thrombus formation
      followed by acute coronary artery occlusion and ischemia is more likely to trigger fatal
      ventricular arrhythmia. We also believe that a precise determination of endothelial cell
      apoptosis, plaque erosion, and systemic and local inflammation could shed light on the
      pathogenic mechanisms prevailing in SCD due to acute coronary artery occlusion. Protection
      and thrombectomy devices were recently developed to avoid distal embolisation during
      angioplasty procedures in saphenous vein graphs or during angioplasty for acute myocardial
      infarction. These devices provide the unique opportunity to harvest blood and thrombi from
      the site of coronary occlusion. The aspirate can be used to study the speed and the intensity
      of local thrombus formation. The use of such techniques could be extended to patients with a
      SCD due to an acute coronary artery occlusion and the data compared to that of patients with
      an acute myocardial infarction without ventricular arrhythmia. Furthermore, markers of
      endothelial cell apoptosis, local and systemic inflammatory biomarkers in the culprit
      coronary artery and in the systemic blood could be studied in such patients and also during
      angioplasty procedures performed in patients with stable coronary lesions.(18-23) The aim of
      the TIDE study (Thrombus and Inflammation in Sudden Death) is therefore to compare the
      composition and age of thrombus collected at the site of coronary occlusion in patients with
      sudden death due to acute coronary artery occlusion and patients with an acute myocardial
      infarction without ventricular arrhythmia. The following hypothesis will be tested : fresh
      thrombus is more frequent in patients with sudden cardiac death versus patients with acute
      myocardial infarction without ventricular arrhythmia. Furthermore, coronary artery and
      systemic blood samples will be drawn in both groups and before coronary angioplasty
      procedures in patients with stable angina pectoris to determine the role of local and
      systemic inflammation and endothelial cell apoptosis in these settings.
    

Intervention name(s): Blood sample
Intervention type(s): Other
Intervention description(s): Blood sample and thrombus sample
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Sudden death; Out of hospital cardiac arrest; Acute myocardial infarction; Acute coronary syndrome