Jan Kajstura

Evidence That Human Cardiac Myocytes Divide after Myocardial Infarction

BACKGROUND The scarring of the heart that results from myocardial infarction has been interpreted as evidence that the heart is composed of myocytes that are unable to divide. However, recent observations have provided evidence of proliferation of myocytes in the adult heart. Therefore, we studied the extent of mitosis among myocytes after myocardial infarction in humans. METHODS Samples from the border of the infarct and from areas of the myocardium distant from the infarct were obtained from 13 patients who had died 4 to 12 days after infarction. Ten normal hearts were used as controls. Myocytes that had entered the cell cycle in preparation for cell division were measured by labeling of the nuclear antigen Ki-67, which is associated with cell division. The fraction of myocyte nuclei that were undergoing mitosis was determined, and the mitotic index (the ratio of the number of nuclei undergoing mitosis to the number not undergoing mitosis) was calculated. The presence of mitotic spindles, contractile rings, karyokinesis, and cytokinesis was also recorded. RESULTS In the infarcted hearts, Ki-67 expression was detected in 4 percent of myocyte nuclei in the regions adjacent to the infarcts and in 1 percent of those in regions distant from the infarcts. The reentry of myocytes into the cell cycle resulted in mitotic indexes of 0.08 percent and 0.03 percent, respectively, in the zones adjacent to and distant from the infarcts. Events characteristic of cell division--the formation of the mitotic spindles, the formation of contractile rings, karyokinesis, and cytokinesis--were identified; these features demonstrated that there was myocyte proliferation after myocardial infarction. CONCLUSIONS Our results challenge the dogma that the adult heart is a postmitotic organ and indicate that the regeneration of myocytes may be a critical component of the increase in muscle mass of the myocardium.

Resident Cardiac Stem Cells

The introduction of stem cells in cardiology provides new tools in understanding the regenerative processes of the normal and pathologic heart and opens new options for the treatment of cardiovascular diseases. The feasibility of adult bone marrow autologous and allogenic cell therapy of ischemic cardiomyopathies has been demonstrated in humans. However, many unresolved questions remain to link experimental with clinical observations. The demonstration that the heart is a self-renewing organ and that its cell turnover is regulated by myocardial progenitor cells offers novel pathogenetic mechanisms underlying cardiac diseases and raises the possibility to regenerate the damaged heart. Indeed, cardiac stem progenitor cells (CSPCs) have recently been isolated from the human heart by several laboratories although differences in methodology and phenotypic profile have been described. The present review points to the potential role of CSPCs in the onset and development of congestive heart failure and its reversal by regenerative approaches aimed at the preservation and expansion of the resident pool of progenitors.

Ventricular Remodeling Following Coronary Artery Constriction and Hypertension

In coronary artery disease in humans, the severity of the atherosclerotic involvement of the coronary circulation frequently does not correlate with the impairment in cardiac pump performance, and therefore anatomic condition is a poor predictor of clinical outcome and mortality of the patient population [1–4]. Based on acute studies in animal models [5], the conclusion has been reached that severe reductions in coronary artery diameter of nearly 80% are required to create an imbalance between oxygen demand and supply, possibly leading to scattered myocardial damage and the initiation of ischemic cardiomyopathy. However, it has recently been shown that coronary artery constriction of moderate degree may induce diffuse myocytolytic necrosis and marked alterations in ventricular hemodynamics [6]. Moreover, the phenomenon of myocyte cell death was documented to persist with time, chronically affecting the functional and anatomical characteristics of the heart [7,8]. Thus, modest decreases in coronary diameter may have clinical implications that have not been previously appreciated, and untreated coronary artery narrowing may progressively affect the structural integrity of the myocardium.