Regenerative and immunological mechanisms in the human heart with an emphasis on heart failure

Abstract

The heart is a complex organ, with musculature, vasculature and many cell types interacting to achieve normal heart function. Chronic heart failure may be caused by factors such as hypertension and ischemic heart disease. Failing hearts are characterized by impaired tissue- and cellular function resulting in inadequate contractile function. Increased understanding of the complex cellular mechanisms is important to improve heart failure treatment. This thesis was, therefore, aimed at characterizing regenerative and immunological mechanisms in the human heart. Flow cytometric (FACS) and gene expression analyses of human heart biopsies were implemented in several of the papers. Paper I was aimed at validating that cellular fixation and other technical factors prior to FACS may be combined with gene expression analysis of adequate sensitivity and quality, which was found to be the case. In Paper II, immature cell populations were characterized in the four chambers of human hearts. The cell populations demonstrated distinct surface marker- and gene expression profiles. SSEA4+CD34‑ cells resembled immature cardiomyocytes that might undergo proliferation. CD45‑ Side Population and C‑kit+CD45‑ cells, on the other hand, resembled immature endothelial cells. Aspects of cardiac immunology were investigated in Papers III-V. In Paper III, the relationship between immunological biomarkers and QRS-T angle width measured through vectorcardiography was investigated. The numbers of white blood cells and neutrophils were significantly higher in individuals with wide QRS-T angles. In Paper IV, the transcriptomic hallmarks of the four chambers of failing and nonfailing human hearts were characterized through RNA sequencing of whole-tissue biopsies. Immunological pathways were enriched for all heart chambers in failing hearts compared to nonfailing hearts. In Paper V, human cardiac mast cells were FACS sorted and analyzed through RNA sequencing. Pathways associated with immunological signaling, fibrosis and remodeling were activated in mast cells in failing hearts.

In conclusion, cell populations and signaling pathways associated with cardiac regeneration and immunology were characterized, thus increasing our knowledge of physiological and pathophysiological mechanisms in the human heart.