Endocardial endothelium (EE) is essential in the embryonic development of the heart, the optimal contractility and rhythm as well as the remodeling of the heart. Endocardial endothelium affect the contractility of cardiomyocytes through paracrine signaling substances such as nitric oxide (NO), endothelin (ET-1), prostaglandins (PGI2, PGF2, PGE2) and angiotensin II (ANG II). Typical lesions of endocardial endothelium have been described in atrial fibrillation, ischemia/reperfusion injury, cardiac hypertrophy, heart failure, sepsis, myocardial infarction, inflammation and thrombosis. In patients with atrial fibrillation, there can be a systemic endothelial dysfunction that combines endocardial and vascular endothelial dysfunction and leads to increased hemodynamic load of the left atrium and increased synthesis and release of natriuretic peptides, angiotensin II, aldosterone and growth factors from the atrial myocardium. A dysfunction of endothelial cells in the local inflammatory status can lead to increased plaque vulnerability, which contributes to plaque rupture and favors the formation of thrombus. Preserving the endocardial-myocardial integrity plays a significant role in the prevention of a coronary artery disease. Endocardial endothelial dysfunction is, similarly to coronary endothelial dysfunction, an early event that leads to the progression of heart failure. Multimarker strategy, that would include a different set of biomarkers, could significantly help in the assessment of patients with cardiovascular diseases. The challenge lays in finding new therapeutic strategies that would, by preserving endothelial function, prevent the onset of cardiovascular diseases.