EECP in the treatment of endothelial dysfunction: Preventing progression of cardiovascular disease

Endothelial dysfunction is a syndrome that encompasses interruption in the barrier function of the vascular endothelium, impairment of control of vascular tone in vasodilation and constriction, failure to provide angiogenic competence, disturbances of antithrombogenic and anti-inflammatory properties, inappropriate regulation of vascular smooth cell proliferation and migration, and breakdown in the reduction of oxidative stress. It is an early marker of cardiovascular events and death, as well as a predictor of atherosclerosis. There are numerous publications in the medical literature documenting endothelial dysfunction and its association with CAD, peripheral vascular disease, hypertension, stroke, heart failure (HF) and diabetes, and it is the link between risk factors such as obesity, insulin resistance, diabetes, smoking, hypertension, hyperlipidemia, inactivity, ageing and genetic predisposition to cardiovascular disease such as CAD, peripheral vascular disease, stroke, HF, renal failure, and complications from diabetes mellitus. Because of the overwhelming evidence associating endothelial dysfunction as precursor of cardiovascular disease, it is extremely important to have an intervention that can provide improvement of endothelial dysfunction and protects against progression of vascular disease processes. Vascular health is preserved through a carefully regulated mechanism that maintains endothelial surface shear forces within a narrow "healthy" physiologic range. Similarly, it has been documented that certain activities, such as exercise, and perhaps EECP, encourage improved endothelial function through modulation of flow-generated endot helial shear stress on the arterial wall. It is the mechanical dragging force acting on the wall of the vessel derived from the friction of the flowing blood, and is proportional to the velocity of blood flow. The shear stress modulates endothelial gene expression through complex mechanoreception and mechanotransduction process, controlling vasomotor tone and other pathophysiological processes responsible for atherosclerosis and vascular remodeling. EECP is a noninvasive circulation assist device for the treatment of patients with CAD. EECP has been shown to be effective in improving exercise capacity, angina functional classes, myocardial perfusion, and quality of life in patient suffering from refractory angina pectoris.^{30, 31} EECP therapy has also been shown to be safe and effective in the treatment of patients suffering from HF.^{32, 33} The hemodynamic effects during EECP treatment have been documented to significantly increase coronary blood flow as well as blood flow in the descending aorta bidirectionally. The increased blood flow increases endothelial shear stress, activating eNOS, an enzyme essential in the synthesis of NO, a powerful endothelium-derived relaxing factor responsible for vascular dilaation, and endothelin-1, a vasoconstrictor. Clinical outcomes of the effects of EECP therapy in the activation of NO have been documented by the increase in RH-PAT and brachial artery flow-mediated dilation in patients with parallel improvement in their angina functional class and status. Improvement in endothelial dysfunction by increasing NO release as a consequence of EECP therapy also leads to the reduction of arterial stiffness documented by decreased pulse wave velocity generated by cardiac output and the magnitude and arrival time of the reflected wave from peripheral vascular sites to the root of the aorta. The reduction of arterial stiffness together with vasodilation of microvasculature leads to a reduction of vascular resistance, SBP and reduced cardiac energy requirements. Improved endothelial function due to EECP therapy also activates angiogenesis growth factors leading to neovascularization with recruitment of collateral circulation, bringing blood flow to regions lacking perfusion due to atherosclerotic occlusion, restoring organ function. EECP therapy also inhibits smooth muscle cell proliferation and migration, reducing intimal hyperplasia, reversing progression of the atherosclerotic process. In addition, EECP therapy reduces plasma inflammatory cytokines and adhesion molecules, markers of future cardiovascular events. All of the research evidence to support the hypothesis that EECP therapy increases shear stress on the endothelium and activates the mechanoreceptors and their signaling pathways that modulates endothelial function and morphology, can prevent future cardiovascular events. Risk factors, genetic predisposition, and low or high shear stress acting on the endothelial cells can all contribute to the development of endothelial dysfunction, leading to premature cell senescence and apoptosis. In addition to increased shear stress to stimulate endothelial cell function, EECP therapy also repairs the damages to the endothelium by mobilizing bone marrow EPC to the peripheral circulation and replacing injured intima. Endothelial dysfunction is the precursor of cardiovascular disease. EECP therapy has been shown to improve various endothelial functions including managing vasomotor control, relaxing arterial stiffness, decreasing vascular resistance and hypertension, promoting angiogenesis competence, inhibiting intimal hyperplasia and smooth muscle cells proliferation and migration, reducing inflammatory and adhesion processes and activating endothelial progenitor stem cells replacing damaged endothelial cells. EECP therapy should be considered as a noninvasive intervention for endothelial dysfunction, and as a powerful preventive therapy for cardiovascular disease.