PHARMED INSTITUTE OF CYBERNETICS
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PHARMED INSTITUTE OF CYBERNETICS |
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PIC Res Comm 2008 May; 5/1 |
A Mechanism of a Metabolic Induction of Coronary Artery Disease in Chronic Kidney Disease |
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Rainer K. Liedtke. MD PIC, Munich, Germany, liedtke@pharmed.de |
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| Abstract | |
| The reasons for the increased incidence of coronary artery disease in patients with chronic kidney disease is still unexplained. Here we present as a possible explanation a model, that, by a reduced activity of ATP-dependent ionic pumps, the intracellular calcium x phosphate product is increased to such an extent that it leads to an increased export of calcium phosphate compounds. These can cause, through chemically replicative mechanisms, a metastatically vascular mineralization. This mechanism would correspond to an early arteriosclerotic development resembling the Mönckeberg’s media calcification and also includes an early phase of hypertension. | |
| Introduction | |
| The link between chronic renal disease (CKD) and vascular calcification, first of all under haemodialysis, is known. It is also known that these patients often show hyperphosphataemia and increased calcium x phosphate product (CaxP). In particular late stages show a strongly progressive vascular calcification with increased cardiovascular mortality [1] due to a coronary artery disease (CAD). In CKD patients with dialysis, the progression of coronary calcification correlated with the prevalence of myocardial infarctions, the length of the dialysis application and the serum concentrations of calcium and phosphate, but not with cholesterol and lipoproteins [2]. Since hyperphosphataemia and/or high CaxP predispose for metastatic calcification, cardiovascular mortality was related to it, too [3]. That way, the therapy of hyperphosphataemia and CaxP was given a central role for lowering cardiovascular risks [4][5], in particular since the coronary calcium score is also a significant risk predictor in dialysis patients [6]. In the calcification initialized in coronaries, the lipid profiles appear to influence neither their initiation nor the progression [2][7]. In the therapy of hyperphosphataemia, the application of phosphate binders containing calcium also led to a higher progression of coronary calcification than that using calcium-free phosphate binders [8][9]. Moreover, that therapy route also showed indications assessed by the authors as anti-atherogenic [10]. But also in persons with healthy kidneys, there was already found a relation between calcium supplementation and increased rates of myocardial infarctions as well as apoplexies [11]. | |
| Relations between chronic kidney disease and media sclerosis and hypertension | |
| The negative context between too high CaxP with CKD and processes of metastatic vascular calcification indicates that the deposit of complex calcium-phosphate crystals, such as hydroxyapatite (HAP) is at least co-responsible for an induction of early arteriosclerotic phases. The initialization of that process appears to be prepared by biomineralization by increased HAP deposit on collagen occurring in the media layer. That is supported by the fact that, in late renal diseases, there is a stronger calcification in the coronary media than in the intima, but also in patients without kidney disease [12][13]. In the same manner, uraemic patients show a significantly more pronounced media thickness and coronary calcification [14]. The initial phase of the process often runs in a sub-clinical manner, wherein the mineralizing structural disorder of elastic proteins in the smooth vascular muscle cells only triggers a "hardening of the arteries" first. Therefore, that provides also a rational approach to the explanation of the formation of hypertension as an early consequential effect of vascular micro-calcification. Calcification of the media moreover was also already found in younger patients without traditional arteriosclerosis risk factors and before the commencement of a haemodialysis treatment, while calcification of the intima was rather found in older patients with a case history of arteriosclerosis [13]. In the same way, an increase in the intima-media thickness of the carotid artery can be found in patients of an advanced age and after a longer duration of the disease [15]. A pathological examination of the morphogenesis of media sclerosis in Mönckeberg’s arteriosclerosis moreover pointed histologically to a process of dystrophic calcification, wherein a higher calcium and phosphor content was found in the compact calcifications [16]. | |
| Cellular Model of progressive vascular calcification | |
| In summary, an inhibition of the mitochondrial oxidative phosphorylation (OXP) by endogenous or exogenous factors, leads to a reduced synthesis of adenosine triphosphate (ATP). It moreover implies the induction of the apoptic Caspase cascade by release of Cytochrome C. Functionally, that leads to a reduced activity of all ionic pumps that receive their energy from the ATP hydrolysis. Therefore, it affects also the Ca-ATPases responsible for the maintenance of low intracellular calcium ions (Ca2+). Of relevance are the membrane-bound plasma membrane Ca2+-transporting ATPase (PMCA) and the sarco(endo)plasmic reticulum Ca2+ ATPases (SERCA). We have already presented a respective overall functional mechanism as the consequence of an OXP inhibition by antiproliferative agents as a model [17]. As a consequence of the disorder of the ATP synthesis, there occurs in summary, on the one hand, an intracellular excess of the ATP precursors not used for phosphorylation and therefore an increase in concentration of phosphate and, on the other hand, there occurs an intracellular (cytosolic and intramitochondrial) accumulation of Ca2+ due to defects in the calcium pumps. As a consequence, an increased amount of phosphates is available to the increased Ca2+ as reaction partner. According to the increased intra-cellular calcium x phosphate product (CaxP), there are increasingly formed, as primary reaction products, calcium phosphates (Ca3(PO4)2). As a consequence of exceeding the saturation conditions, the latter in part deposit in a crystalline form. That again leads, in a further step, to an increased crystalline complex formation of hydroxyapatites (HAP) (Ca5(PO4)3OH). The deposited HAP serve as replicative matrixes for the production of further HAP crystals within the meaning of a "chemical self assembly". By cell disruption or also exocytosis, a further export of HAP may occur. Its crystalline deposit on the tissue occurs on the collagen of the media layer first where it causes a stiffening of the collagen fibres. Also the externally deposited HAP again serves as replicative matrixes. Through that vicious circle, the degenerative process in the collagen of vascular myofibrils extends further and induces a further vascular calcification. That kind of metastatic biomineralization implies, apart from the extension, also an acceleration of these processes (Figure 1). At first and within the meaning of histological micro-calcification, the myofibrillar calcifications only cause a thickening and stiffening of the media. Therefore, they continue first to be sub-clinical and so to speak form a latent | |
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| Figure 1. Descriptive schematic representation of the consequences of an inhibition (–II) of the mitochondrial oxidative phosphorylation (OXP) on calcium ions and phosphates. Initially, there is found an increased intracellular calcium x phosphate product ([PO43-][Ca2+]) from which increasingly calcium phosphates (Ca3(PO4)2) are formed which leads to an increasing formation and crystalline deposition of hydroxyapatites (Ca5(PO4)3OH). The latter serve as replicative matrixes for further hydroxyapatite complexes ("chemical self-assembly") that metastatically cause a collagen-associated mineralization of the arterial media with vascular stiffening CAD: Coronary Artery Disease (modified excerpt from [17]). | |
| early phase of "local hypertension". That kind of induced vascular calcification altogether appears to be a process having some similarities with bone mineralization. In the course of the then replicatively extending biomineralization, however, there is to be expected an increasing occurrence of systemic effects ("avalanche effect") with increasing brittleness and intima immigration. That may also result in the more intravascular processes like plaque formation and its known clinical consequences. | |
| The chemical self assembly of HAP appears important for the spread and progression of the clinical outcome. This kind of spontaneous formation of supramolecular structures in the body is presumably an own and separate physico-chemical process which includes calcium ions and organic ligands. Some basic processes of the crystalline nucleation and technical in-vitro assessments on the mechanism of HAP self assembly in simulated body fluid have been described [18][19][20]. Studies were also made on composites with collagen, which complied biologically with extracellular matrix fibers [21] or bone structures [22][23]. An important aspect for a biological apatite nucleation and its expansion, appears the contribution of extracellular matrix proteins which bind calcium ions. Technically of importance for the HAP self assembly are also the composition of phosphates [24, the conditions of chemical saturation [25] and the pH. Since this chemical process is different to usual cellular biochemical processes it appears in part uncoupled from a direct biological feed-back. At least some of the early phases of the cellular calcification appear still below the radar screen of hormonal control. The latency of the early processes, its chemical nature, and a lack of specific biomarkers, complicate a clinical approach. The metastatic phase can be in sum considered a chemical-stoichiometrical process, however based on this it also offers a therapeutic chance of an intervention. | |
| Conclusion | |
| Metastatic calcification with coronary artery disease in patients with a chronic renal disease presumably is originally caused by too high intracellular calcium x phosphate product from which the increased formation of calcium phosphates results that, on their part, cause the formation of chemically replicative matrixes for hydroxyapatites. The replicative formation of hydroxyapatites in principle forms an autonomous and spontaneous formation of supramolecular structures (chemical self-assembly). Accordingly, only, or at least in its majority, the disseminated hydroxyapatites induce further vascular calcification. Altogether, from an at first latently accumulating cellular calcium/phosphate imbalance, there may recruit the formation of compounds with a calcifying-degenerative effect that then spread replicatively in an avalanche-like manner. Under the same metabolic aspect, that seems to be also the case with regard to an early hypertension resulting from these processes. | |
| References | |
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© 2010 Rainer K. Liedtke |