What is the role of stem cell treatment of a heart attack: non-STEMI? Non-STEMI or Non-ST elevation Myocardial Infarction is the dominant presentation of acute coronary syndrome. This occurs when the blood supplied to the heart muscle is suddenly blocked. Other presentations include unstable angina and STEMI or ST-Elevation Myocardial Infarction. Patients presenting with symptoms of chest pain with or without accompanying symptoms of shortness of breath, profuse sweating, nausea or syncope, and have evidence of myocardial necrosis (elevation of cardiac enzyme: troponin) with absence of ST elevation are considered to have a Non-STEMI. ST segment depression, transient ST elevation or deep T-wave inversion on the electrocardiogram may be present but are not necessary. This was well described by my colleague Dr Mustafa Ahmed in the article on NSTEMI?
Stem cells in the treatment of a heart attack: What is the problem with a Non-STEMI?
Each year, it is estimated that almost 800,000 patients will experience an acute coronary syndrome of which 70% will have a Non-STEMI. Trends from the world data base of patients with acute coronary syndrome show that the percentage of patients with Non-STEMI is rising dramatically. Acute coronary syndrome is caused by plaque rupture or erosion with different degrees of superimposed thrombus or clot resulting in a decreased blood flow to the heart muscle. In most cases, the damage to the heart muscle is limited to the most inner layers of the myocardium and for this reason a Non-STEMI is called a minor or small heart attack. However, patients with Non-STEMI have more comorbidities, both cardiac and noncardiac. The patients are older (median age of 68), and they more often have had a previous MI, congestive heart failure, atrial fibrillation, diabetes and abnormal kidney function. The in-hospital mortality of Non-STEMI and STEMI is similar ( approx. 4%) but by 12 months, patients with Non-STEMI have an increased risk of myocardial infarction, death and recurrent instability. Early events are related to recurrent plaque rupture and thrombus and late events are closely related to left ventricular dysfunction and heart failure.
Stem cells in the treatment of a heart attack: What is the conventional treatment of a Non-STEMI?
Upon presentation, the clinical history, angina symptoms and equivalents, physical exam, ECG, renal function and cardiac troponin can be integrated into an estimation of the risk of death and complications of ischemic events. The patient with a high risk, continuing chest pain, hemodynamic instability (decrease in blood pressure or worsening heart failure) and uncontrolled arrhythmias (such as ventricular tachycardia) should be treated with anticoagulants, antiplatelets and treated with an invasive approach where the patient is taken to the cath lab for percutanous coronary intervention and coronary stenting if appropriate. Below is an example of a patient with Non-STEMI that was treated with coronary angioplasty and stenting of the circumflex artery. Notice that he had also a chronic occlusion of his right coronary artery with collaterals originating from the same circumflex artery. The area of ischemia was very significant.
Medications required in hospital for control of angina should be continued after hospital discharge. This may include nitrates, beta blockers, calcium antagonists and antiplatelets such as aspirin, clopidogrel, prasugrel or ticagrilor. Patients with heart failure should be treated with angiotensin converting enzyme inhibitors or angiotensin receptor blockers. These medications will help preserve the left ventricular function and prevent further decompensation of their heart failure. Patients should be treated with appropriate cholesterol management including statin, blood pressure control, smoking cessation and lifestyle changes.
Stem cells in the treatment of a heart attack: What is their role in a Non-STEMI?
During the Non-STEMI, prolonged ischemia causes myocardial cell death and progressive loss of heart muscle and contractile tissue. Cardiac cells possess minimal ability to regenerate themselves. The myocardial cells are replaced by scar tissue. Subsequently, these changes lead to left ventricular remodeling resulting in an enlargement of the heart and development of heart failure. The goal of stem cell therapy for subjects with a Non-STEMI is to improve cardiac function in an attempt to decrease the development and onset of congestive heart failure.
Multistem® is a multipotent adult progenitor cell product developped by Athersys, Inc. (Cleveland, Ohio). The stem cells are isolated from human bone marrow. The stem cell cultures can be expanded and used off the shelf for treatment of a variety of disease including myocardial infarction. Preclinical data of myocardial infarction demonstrated an improvement of left ventricular function 2-6 weeks post cell injection. Additionally, there was a significant increase in blood vessel around the infarct zone. In the phase 1 clinical trial, 19 patients were given a Multistem® intracoronary injection 2-3 days after their heart attack. All the patients studied had a STEMI. One of those patients was described in our previous article: “Surviving a heart attack: the big one“. Not only did he have an improvement of his heart function, but he had developed collaterals that prevented him from having further damage to his heart when his “widowmaker” proximal LAD reoccluded five years later. Patients that were treated with the higher dose of Multistem® had a 25% improvement of left ventricular function measured by echo at 4 months post treatment over baseline. These changes persisted at 1 year with an increase of 11% over baseline. Below is another example of a patient that underwent Multistem® injection in 2009. Fifty million stem cell dose were injected through the right coronary artery 3 days after presentation with an inferior STEMI and PCI with coronary stenting of his coronary artery (RCA).
Stem cells in the treatment of a heart attack: MRI to assess myocardial viability in a non-STEMI
MRI infarct size is an important predictor of mortality and major cardiovascular events. MRI spatial resolution allows for the detection of subendocardial infarcts. It correlates well with histology and PET scanning.
To perform MR imaging, we used a 1.5T whole body scanner (GE 450 Widebore at BBH Princeton) and a phase array body coil that is wrapped around the patient’s chest. Some of our patients are claustrophobic and for the study, one of our research nurses usually has to stay with the patients. The protocol starts with anatomical stack localizer scout imaging to determine the orientation of the left ventricle short axis imaging plane. For evaluation of the left ventricular function, cine MR imaging is performed using ECG modified gated gradient echo sequences and breath-holding technique. This results in dynamic images with high temporal resolution that allows for evaluation of the left ventricular wall motion and volume measurements. This is performed in collaboration with Dr Ricardo Bracer and our Radiology department. Below is an example of a patient with a non-STEMI involving a stenosis of the mid LAD that was treated with coronary stenting.
The MRI study performed immediately after coronary stenting and randomization into the Athersys protocol demonstrated significant anteroapical hypokinesis and LV dysfunction.
Six months later, the patient underwent repeat MRI showing significant improvement when compared to baseline. The patient is followed as part of the Athersys study. It is unknown at this time whether the patient received stem cell treatment versus control.
For imaging the myocardial infarct, the MRI protocol uses a special sequence called Inversion Recovery combined with a contrast agent called Gadolinium (Magnevist). Contrast agents do not accumulate in normal heart cells (e.g. myocytes) but rather accumulate in the extracellular space or into damaged, ruptured myocytes. Therefore, the presence of gadoliniumt can be used to assess infarcts of the myocardium and other myocardial disease. So, 10 minutes after bolus injection, delayed images are acquired using a sequential T1-weighted Inversion Recovery turboflash sequence, with a variable T1 delay adjusted for each patient. The optimized choice for Inversion Recovery time “nulls” the signal of the normal myocardium. This optimization also depends on the contrast dose which varies according to the patient’s weight and kidney function. The delayed enhancement images are then obtained 15 mins after intravenous injection with the patient holding their breath for 15 seconds. During that time a minimum of 12 slices covering the whole heart are acquired.
Stress myocardial perfusion imaging is performed using intravenous (iv) adenosine as a stress agent. Four minutes after starting the iv infusion of adenosine, iv gadolinium contrast is administered followed by acquisition of a spoiled gradient echo stress perfusion scan in the short and long axis of the heart before contrast reaches the left ventricular cavity. This allows us to assess the perfusion enhancement of the myocardium. Fifteen minutes after stopping adenosine, we acquire a rest perfusion scan using similar imaging technique. The infusion of adenosine can increase the myocardial blood flow up to 5 times normal in patients without coronary obstruction. The ratio of measured myocardial blood flow obtained with resting baseline and with maximal hyperemia (during adenosine infusion) provides an estimate of myocardial perfusion reserve. This can provide an assessment of the myocardium at jeopardy by identifying inducible ischemia and can predict recovery of myocardial function after myocardial infarction and revascularization with PCI. Below is an example of myocardial perfusion at rest.
Stem cells in the treatment of a heart attack: a patient with a non-STEMI
We are currently participating in a phase II prospective, randomized, double-blind, sham-controlled, multi-center clinical trial designed to assess the safety of AMI Multistem® in patients with Non-STEMI. Dr Farrell Mendelsohn is the principal investigator at BBH Princeton. Patients are randomized and treated no later than 3 days after their myocardial infarction. One of our patient had his first heart attack at the age of 26. Two years later he had his second heart attack. He had a lot of stress in his life, going through a divorce. Four months prior to his third heart attack, his ex-wife was killed in a car accident and he became solely responsible for the care and well-being of his seven year old daughter. He realized that he had to get better for his daughter. So when Dr Hutton Brantley, one of our investigators, approached him about participating in the AMI Multistem® trial, he did not hesitate! The AMI Multistem® trial is currently enrolling patients with Non-STEMI across the United States. If you would like more information, please refer to clinicaltrials.gov.