One of the most frequent questions our patients ask after surviving a heart attack is: Can heart attack damage be reversed?

Every year, over 700,000 Americans have a heart attack. Improvements in the treatment of myocardial infarction, especially with the reopening of the culprit artery with percutaneous coronary intervention, have led to a large number of heart attack survivors. During the acute phase of the heart attack, the artery is occluded by a thrombus or clot. Below is an example of a patient with a widow maker heart attack. The proximal LAD is completely occluded.

In addition, medical therapy with ace inhibitors/angiotensin receptor blockers and beta blockers can limit certain maladaptive pathways that could lead to infarct expansion. On the other hand, regenerative medicines could lead to shrinking of the scar and prevent the development of clinical heart failure.

Can heart attack damage be reversed? Experimental studies.

In the last decade, the recognition that adult hearts undergo a constant regeneration of its cellular components has created new opportunities for treatment of heart disease. This regeneration machinery resides with stem cells located within the heart. These stem cells can transform into heart muscle (myocytes) or blood vessels (smooth muscle, endothelial cells). In most animal models, the occlusion of an artery leads to damaged myocardium and is replaced by a scar, just like in humans. Zebra fish fully regenerate their heart muscle within 2 weeks after more than 20% of their hearts have been resected. These incredible regenerative properties are also shared by the newt. This enviable regenerative capability has generated a lot of enthusiasm in stem cell research. Various types of stem cells have been used for myocardial regeneration. In this report, we will look atcardiospheres derived cells.

Can heart attack damage be reversed by Cardiospheres derived cells (CDCs)?

Cardiospheres describes a cluster of endogenous cardiac stem cells that form when the cells are cloned. Samples of heart muscle are obtained by biopsies of heart tissue and then grown in culture to yield millions of Cardiospheres derived cells (CDCs) that can later be injected intravenously or intracoronary. These stem cells can differentiate into heart muscle and blood vessels (such as collateral’s seen in patients with coronary disease). Research has demonstrated however, that the therapeutic action of CDCs does not depend on their capacity to engraft and differentiate, but from their ability to stimulate endogenous repair. The release of growth factors triggers regeneration of heart cells and inhibits cell death and fibrosis resulting in improvement in muscle function. In preclinical models of heart attack, they have been shown to reduce the scar size, regenerate cardiac muscle and improve myocardial function.

In a phase 1 clinical trial, CDC autologous (from the same patient) stem cells were obtained from endomyocardial  biopsies of the patients 2-4 weeks after their heart attacks. The CDCs were grown according to the cardiospheres culture method and injected into the infarct related artery one and half to 3 months after their heart attacks. Infarct size was assessed by Magnetic Resonance Imaging (MRI). The patients treated with CDCs showed a reduction in scar mass and increase in viable heart mass and regional wall motion.

Can heart attack damage be reversed by CDCs? the ALLSTAR clinical trial

Obtaining heart muscle tissue with endomyocardial biopsies can be quite cumbersome for the patients. In addition, there are no guaranties of cell integrity. Some cell samples may not be suitable for clinical use. When heart samples are obtained from an Organ Procurement Organization, a master cell bank can be created. Harvested cells grown from this tissue can be used as an allogeneic (other people) version of CDCs or CAP-1002 (Capricor). In preclinical studies, these allogeneic CDCs have been demonstrated to be safe and the efficacy profile of CAP-1002 was indistinguishable from prior studies using autologous CDCS.

The principal goal of phase I/II ALLSTAR clinical trial was to establish the safety of intracoronary infusion of allogeneic stem cells,CAP-1002, in patients with ischemic left ventricular dysfunction (EF less or equal to 45%), 4 to 12 months after a large anterior myocardial infarction.

The secondary objective was to evaluate whether intracoronary infusion of CAP-1002 resulted in structural cardiac or functional clinical benefits in these patients. After a baseline cardiac MRI, patients were randomly allocated to receive CAP-1002 infused through an over-the-wire angioplasty balloon catheter inflated at the start site of the previous blockage of the infarct related artery. Cells were infused over 15 minutes, in 3 boluses of 25 million CDCS each. The angiogram below represents a typical patient enrolled in the study.

The MR imaging protocol is pretty daunting and the adherence to a standardized methodology cannot be overemphasized. For the ALLSTAR study, 30 centers participated and enrolled patients. Enrollment into the study occurred early in our cardiac MR imaging experience . Thanks to the involvement of our radiology department at BBH Princeton with Dr Ricardo Bracer and the radiology technicians, we were able to perform good quality MR imaging studies. Several centers enrolled fewer than 5 patients while some others had more than 15 patients enrolled. In total, 134 patients received the CDC’s and 44 received placebo and underwent follow up MR imaging studies at 6 and 12 months.

For imaging the myocardial infarct, the MRI protocol used a special sequence called Inversion Recovery combined with a contrast agent called Gadolinium (Magnevist in ALLSTAR).  contrast agents do not accumulate in normal intact heart cells (e.g. myocytes) but rather accumulate in the extracellular space or into damaged, rupture myocytes. Therefore, the presence of Gadolinium enhancement can be used to assess infarcts of the myocardium and other myocardial disease.  Ten 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. Below are the images of our same patient demonstrating a short axis view depicting the infarct (left panel) and where the slice was obtained from the LV (right panel) at baseline and at 12 months in 2 representative levels in that same patient.

Artifacts caused by sub-optimal breath holding technique and patient motion, also referred to as “ghosting artifacts”, can significantly affect the image quality of the study. Inability to obtain an adequate inversion time (T1) can also affect the study, resulting in inadequate nulling of normal myocardium and making detection of abnormal enhancement difficult.  This can result in underestimation of the infarct size or extent of the disease. The presence of metal, such as surgical clips, stents and ICD’s can also cause artifact and degrade the image quality to almost non-interpretable. Some software application can be used to compensate for these artifacts but there are not perfect. Finally, gaps in acquisition through the heart can result in underestimation of the left ventricular mass and/or infarct size. So as you can see, there are a lot of technical and patient factors that can influence the accuracy of infarct size evaluation by MRI.

The ALLSTAR study set out to test whether Cardiospheres-derived cells can reduce infarct size, 3-12 months after a large anterior myocardial infarction. Below represent the infarct at baseline and at 12 months on 2 representative slices on the same patient. The red arrows are pointing to the primary area of the anteroseptal wall  infarction. Notice also a small inner layer of brightness at 2 and 3 o’clock indicating an area of subendocardial infarction involving the anterolateral wall. Finally, the area of increased brightness at 5 o’clock represent a previous infero-lateral infarct.