Association between atherosclerosis and the development of multi-organ pathologies

Abstract

Atherosclerosis is a chronic inflammatory disease affecting the vascular system, characterised by the accumulation of modified lipoproteins, immune cell aggregation and the development of fibrous tissue within blood vessel walls. As atherosclerosis impacts blood vessels, its adverse effects may manifest across various tissues and organs. In this review, we examine the association of atherosclerosis with Alzheimer's disease, stroke, pancreatic and thyroid dysfunction, kidney stones and chronic kidney diseases. In several cases, the reciprocal causative effect of these diseases on the progression of atherosclerosis is also discussed. Particular attention is given to common risk factors, biomarkers and identified molecular mechanisms linking the pathophysiology of atherosclerosis to the dysfunction of multiple tissues and organs. Understanding the role of atherosclerosis and its associated microenvironmental conditions in the pathology of multi-organ disorders may unveil novel therapeutic avenues for the prevention and treatment of cardiovascular and associated diseases.

Keywords: Alzheimer’s disease; Atherosclerosis; chronic kidney disease; kidney stones; stroke; thyroid dysfunction.

Figure 1.

Potential pathophysiological mechanisms connecting atherosclerosis and stroke thought the common risk factors (diabetes, metabolic syndrome and hypertension). Oxidative stress and chronic low-grade inflammation are the main processes leading to endothelial dysfunction and arterial stiffness, and, eventually, resulted in atherosclerosis. Subsequently, atherosclerosis progression may lead to thrombosis, formation of unstable plaques and stenosis of blood vessels, which greatly increase the risk of stroke and other cardiovascular events. Post-stroke dementia is a common condition of stroke survivors, seen at a high rate shortly after stroke.

Figure 2.

Interplay between cardiovascular risk factors and increased risk of Alzheimer’s disease. Hypertension can increase β-amyloid (Aβ) deposition and aggravate Aβ-induced cerebrovascular dysfunction. Also, hypertension could impair Aβ vascular clearance and increase its cleavage from the amyloid precursor protein (APP). Finally, hypertension can cause white matter injury, microbleeds, microinfarcts and facilitate development of cerebral atherosclerosis, which manifests by ischaemic stroke, chronic hemispheric hypoperfusion or cerebral hypoxia, thus triggering AD development. Diabetes and metabolic syndrome associated with AD through several underlying mechanisms, such as hyperglycaemia-induced toxicity, advanced glycation end product-induced adverse effects, insulin resistance, insulin receptor impairment, inflammation and cerebrovascular damage. Also, dyslipidaemia increased Aβ peptide deposition, promotes Tau hyperphosphorylation, compromised the integrity of the blood–brain barrier and promote neuroinflammation compatible with AD. The role of ASCVD in AD progression is depicted in solid lines; the role of AD in the progression of ASCVD is depicted in dashed lines. Aβ: amyloid β; APP: amyloid precursor protein; CAD: coronary artery disease; HF: heart failure; AF: atrial fibrillation.

Figure 3.

The complex relationship between diabetes, metabolic syndrome, non-alcoholic fatty liver disease (NAFLD), non-alcoholic fatty pancreatic disease (NAFPD), and atherosclerosis. In the conditions of obesity and diabetes, the increased secretion of free fatty acids (FFA) from adipose tissue to the circulation lead to increased delivery of FFA to the pancreas and the liver. In the liver, the surplus of FFA facilitated the development of NAFLD and increased the production of very-low-density lipoproteins, which promoted the development of NAFPD. Also, metabolic syndrome, obesity and diabetes are associated with systemic low-grade inflammation and increased oxidative stress, which, altogether with β-cell lipotoxicity caused by a fat accumulation in the pancreas, leading to the vicious cycle that further aggravates metabolic diseases and NAFPD. Several shared risk factors connected discussed disease with higher risk for the development of atherosclerosis and other cardiovascular diseases.

Figure 4.

The role of CKD-associated pathological changes in the increased risk of atherosclerosis and other cardiovascular diseases. CKD-specific primary pathologic changes (such as uraemic toxins, albuminuria, anaemia and others) (depicted in fuchsia box) lead to secondary damage to cardiovascular system (such as endothelial dysfunction, oxidative stress and others) (depicted in magenta box) which lead to the remodelling of the myocardium and blood vessels (depicted in red box). These processes further contribute to the development and progression of atherosclerosis and other cardiovascular diseases.

Figure 5.

Mechanism of kidney stone formation. Unbalance diet (such as oxalate-rich diet) or genetic factors caused hyperoxaluria, hypercalciuria, hypocitraturia, hyperuricosuria or hyperuricosuria. Subsequently, these factors lead to the supersaturation of salts such as CaOx or uric acid or CaP, their nucleation, growth, aggregation and retention in the arterial wall, which resulted in kidney stone formation. Surplus ROS is formed by high uric acid or high oxalate, caused renal injury and promoted crystal nucleation and aggregation, thus facilitating kidney stones formation.

Figure 6.

The summary of the pathogenic mechanisms connecting the increased risk of atherosclerosis development in hypothyroidism. Thyroid hormones regulate food intake, metabolism of lipids and glucose, thus affecting energy homeostasis and body weight. Increased adiposity caused hyperleptinaemia, which stimulated TSH secretion, which, in turn, promoted a differentiation of pre-adipocytes into adipocytes, thus closing the vicious cycle. Obesity is often accompanied by insulin resistance, which can stimulate leptin release and lead to hyperleptinaemia. The increased production of inflammatory cytokines in obesity reduced iodide uptake and may induce thyroid gland malfunction. Additionally, the described processes negatively affected blood vessels, causing endothelial dysfunction and arterial stiffness, and thus facilitating development of atherosclerosis and other cardiovascular diseases. The direct effects of thyroid hormones on heart rate, blood pressure, homocysteine levels and coagulation system are another processes increasing risk of ASCVD.