More than half of all deaths among end stage renal disease (ESRD) patients are due to cardiovascular disease (CVD). Cardiovascular changes secondary to renal dysfunction, including fluid overload, uremic cardiomyopathy, secondary hyperparathyroidism, anemia, altered lipid metabolism, and accumulation of gut microbiota-derived uremic toxins like trimethylamine N-oxidase, contribute to the high risk for CVD in the ESRD population. In addition, conventional hemodialysis (HD) itself poses myocardial stress and injury on the already compromised cardiovascular system in uremic patients. This review will provide an overview of cardiovascular changes in chronic kidney disease and ESRD, a description of reported mechanisms for HD-induced myocardial injury, comparison of HD with other treatment modalities in the context of CVD, and possible management strategies.

/pdf/hemodialysis-induced-cardiovascular-disease-joh31ybk7z.pdf

Hemodialysis-induced cardiovascular disease.

Despite best evidence-based treatment including statins, residual cardiovascular risk poses a major challenge for clinicians in the twenty first century. Atherogenic dyslipidaemia, in particular elevated triglycerides, a marker for increased triglyceride-rich lipoproteins and their remnants, is an important contributor to lipid-related residual risk, especially in insulin resistant conditions such as type 2 diabetes mellitus. Current therapeutic options include peroxisome proliferator-activated receptor alpha (PPARα) agonists, (fibrates), but these have low potency and limited selectivity for PPARα. Modulating the unique receptor–cofactor binding profile to identify the most potent molecules that induce PPARα-mediated beneficial effects, while at the same time avoiding unwanted side effects, offers a new therapeutic approach and provides the rationale for development of pemafibrate (K-877, Parmodia™), a novel selective PPARα modulator (SPPARMα). In clinical trials, pemafibrate either as monotherapy or as add-on to statin therapy was effective in managing atherogenic dyslipidaemia, with marked reduction of triglycerides, remnant cholesterol and apolipoprotein CIII. Pemafibrate also increased serum fibroblast growth factor 21, implicated in metabolic homeostasis. There were no clinically meaningful adverse effects on hepatic or renal function, including no relevant serum creatinine elevation. A major outcomes study, PROMINENT, will provide definitive evaluation of the role of pemafibrate for management of residual cardiovascular risk in type 2 diabetes patients with atherogenic dyslipidaemia despite statin therapy.

/pdf/pemafibrate-k-877-a-novel-selective-peroxisome-proliferator-nj82d9yhio.pdf

Pemafibrate (K-877), a novel selective peroxisome proliferator-activated receptor alpha modulator for management of atherogenic dyslipidaemia

Inflammatory mechanisms may be involved in atherosclerotic plaque rupture. By using a novel histology-based method to quantify plaque instability here we assess whether the activation of the lectin complement pathway (LP), a major inflammation arm, could represent an index of plaque instability. Plaques from 42 consecutive patients undergoing carotid endarterectomy were stained with hematoxylin-eosin and the lipid core, cholesterol clefts, hemorrhagic content, thickness of tunica media and intima, including or not infiltration of cellular debris and cholesterol, were determined. The presence of ficolin-1, -2 and -3 and mannose-binding lectin (MBL), LP initiators, was assessed in the plaques by immunofluorescence and in plasma by ELISA. LP activation was assessed in plasma by functional in vitro assays. Patients presenting low stenosis (≤75%) had higher hemorrhagic content than those with high stenosis (>75%), indicating increased erosion. Increased hemorrhagic content and tunica media thickness, as well as decreased lipid core and infiltrated content were associated with vulnerable plaques and therefore used to establish a plaque vulnerability score that allowed to classify patients according to plaque vulnerability. Ficolins and MBL were found both in plaques’ necrotic core and tunica media. Patients with vulnerable plaques showed decreased plasma levels and intraplaque deposition of ficolin-2. Symptomatic patients experiencing a transient ischemic attack had lower plasma levels of ficolin-1. We show that the LP initiators are present within the plaques and their circulating levels change in atherosclerotic patients. In particular we show that decreased ficolin-2 levels are associated with rupture-prone vulnerable plaques, indicating its potential use as marker for cardiovascular risk assessment in atherosclerotic patients.

/pdf/lectin-pathway-of-complement-activation-is-associated-with-prc85xvf8p.pdf

Lectin Pathway of Complement Activation Is Associated with Vulnerability of Atherosclerotic Plaques.

High rate of early restenosis after carotid eversion endarterectomy in homozygous carriers of the normal mannitose-binding lectin genotype

Stroke is associated with vascular events that follow the initial insult and involve the activation of several blood-borne cascades including coagulation, contact/kinin, and complement cascade. There is growing evidence implicating the complement system as a co-ordinator of these cascades in brain ischemia.1–4 Although full complement cascade activation leads to cell lysis, complement components activated along the cascade (upstream of the final event) have active parts in inflammatory processes, implying they are in intimate cross talk with the other systems.

The complement system is a physiological component of innate immunity, which is activated on recognition of danger signals, the so-called damage-associated molecular patterns, in addition to pathogen-associated molecular patterns.5–7 Damage-associated molecular patterns include glycoproteins and proteins from the extracellular matrix, intracellular proteins, DNA or RNA fragments, and heat-shock proteins, all produced when tissue homeostasis is altered by pathological condition. Different signals lead to the activation of different complement activation pathways, namely, the classical (activated on binding antibodies, C-reactive protein, apoptotic cells, and nucleic acids), lectin (LP, activated on recognition of carbohydrate patterns), alternative (constitutively active and working as an amplifying loop of complement) and extrinsic (activated by tissue factor, and thrombin) pathways, all generating cleaved active fragments by cascade-like proteolytic reactions.6,8

The LP seems to have a vital role in brain ischemia.6 This pathway depends on initiator molecules including mannose-binding lectin (MBL), ficolin-1, -2, and -3, and collectin-11 that can recognize and bind carbohydrates exposed on the surface of altered or damaged cells, including endothelial cells.6 They normally circulate complexed with MBL-associated serine proteases (MASPs). On binding to their ligands, the complexes become activated, promoting downstream complement activation.9 LP active complexes can also cleave coagulation factors and may, thus, directly contribute to thrombosis.1,4,10

Here, …

Lectin Complement Pathway and Its Bloody Interactions in Brain Ischemia

Introduction. Mannose-binding lectin (MBL) activates complement system and has been suggested to play a role in vascular complications in diabetics. Carotid intima-media thickness (cIMT) detects subclinical atherosclerosis. We evaluated the association of MBL and IMT in type 2 diabetic (T2DM) patients. Methods. Serum MBL levels and cIMT were measured in a total of 103 diabetics and in 98 age-matched healthy controls. Results. There was no significant difference in MBL level in T2DM versus controls. As expected, IMT was significantly higher in T2DM patients than in controls (). In T2DM, the lowest cIMT was seen in patients with normal MBL level (500–1000) while cIMT continuously increased with both high MBL and absolute MBL deficiency states. This was especially significant in high MBL versus normal MBL T2DM patients (). According to multiple regression analysis the main predictors of IMT in T2DM are age (), ApoA level (), and the MBL (). Conclusions. Our results suggest a dual role of MBL as a risk factor for cIMT in T2DM. MBL may also be used as a marker of macrovascular disease, as both low and high levels indicate the susceptibility for atherosclerosis in T2DM.

/pdf/mannose-binding-lectin-levels-and-carotid-intima-media-3dgq60w1rt.pdf

Mannose-Binding Lectin Levels and Carotid Intima-Media Thickness in Type 2 Diabetic Patients

Renal replacement therapy may have a favorable effect on diastolic left ventricular function, but it is not clear whether hemodiafiltration is superior to hemodialysis in this field. Nitric oxide (NO) and asymmetric dimethylarginine (ADMA) may play a role in the changes of intracardiac hemodynamics, but it is not clear whether the different renal replacement methods have disparate influence on the metabolism of these materials. Thirty patients on renal replacement therapy were investigated. First, data was analyzed while patients received hemodiafiltration over a period of three months. Then, the same patients were evaluated during treatment with hemodialysis for at least another three months. Echocardiography was performed before and after renal replacement therapy. No significant difference was found in the volume removals between hemodialysis and hemodiafiltration. The left atrial diameter and transmitral flow velocities (E/A) decreased significantly only during hemodiafiltration. A positive correlation was observed between the left atrial diameter and E/Ea representing the left ventricular pressure load during hemodiafiltration. Significant correlations between NO and A and E/A were observed only in the case of hemodiafiltration. Hemodiafiltration has a beneficial effect on echocardiographic markers representing left ventricular diastolic function. This could be attributed to the differences between the dynamics of volume removal and its distribution among liquid compartments.

/pdf/hemodialysis-and-hemodiafiltration-differently-modulate-left-46kublt22y.pdf

Hemodialysis and hemodiafiltration differently modulate left ventricular diastolic function

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Mannose-Binding Lectin Levels and Carotid Intima-Media Thickness in Type 2 Diabetic Patients

Hemodialysis and hemodiafiltration differently modulate left ventricular diastolic function