Morphological Substrates of Atrial Fibrillation and Cardiovascular Mortality: Focus on Autonomic Nervous System, Collagen, and Vasculature

Atrial fibrillation, characterized by irregular and rapid heartbeats originating from the atria. It poses a significant healthcare challenge as the primary cardiac cause of stroke. The autonomic nervous system regulates heart rate and contractility, focusing on the balance between sympathetic and parasympathetic nerves, and plays a role in the pathophysiology of cardiac arrhythmias. This project focused on comprehensive analysis of morphological and immunohistochemical arrhythmogenic substrates in individuals with and without a history of atrial fibrillation. The focus included the density of sympathetic and parasympathetic nerve fibers and ganglia in various cardiac regions. Additionally, blood and lymphatic vessel density, along with the extent of interstitial myocardial collagen were analyzed. All morphometric data were correlated with clinical data. The studied regions included myocardial sleeves around caval and pulmonary veins, the vein of Marshall, and the cardiac conduction system. Samples were analyzed using morphometric software with machine-learning functions.

In Publications I-III, we revealed associations between autonomic nerve density and cardiovascular mortality. Sympathetic denervation in pulmonary veins was evident in subjects with an immediate cardiovascular cause of death. However, increased parasympathetic nerve density in atrial-pulmonary vein ostia was observed in subjects with underlying cardiovascular causes of death. Decreased nerve density of myocardial sleeves around superior vena cava was associated with increased mortality in individuals with cardiovascular diseases. No association in autonomic nerve density was found in the myocardial sleeves around caval and pulmonary veins between subjects with and without atrial fibrillation. Significant changes in sympathetic innervation and neural growth around the vein of Marshall were associated with atrial fibrillation, myocardial infarction, and cardiovascular cause of death. Moreover, aging was associated with increased interstitial fibrosis. In Publication IV, we studied vasculature, innervation, and collagen in the cardiac conduction system. Collagen around the cardiac conduction system was increased. Additionally, lymphatic vasculature, overall innervation, and neural growth were increased in the cardiac conduction system. These changes might influence the normal cardiac function.

Our findings enhance understanding of the distribution of cardiac autonomic innervation, vasculature, and collagen. The studies establish a morphological reference for future research focusing on arrhythmias and other cardiac conditions, offering insights that could influence the development of novel therapeutic and diagnostic approaches.