Risto Tertti

Intravenous administration of low molecular weight and unfractionated heparin elicits a rapid increase in serum pregnancy-associated plasma protein A.

BACKGROUND Pregnancy-associated plasma protein A (PAPP-A) has been suggested as a useful diagnostic and prognostic marker in acute coronary syndromes. Because low molecular weight heparin (LMWH) and unfractionated heparin (UFH) are commonly used in these cases, we analyzed the effects of intravenous administration of these heparins on serum PAPP-A concentrations. METHODS Serum concentrations of total and free PAPP-A were analyzed in 14 patients on chronic hemodialysis and in 10 coronary angiography patients. Ten of the dialysis patients received standard LMWH anticoagulation at the start of dialysis, and 4 were treated with a heparin-free method. Two of the patients on heparin-free hemodialysis received a reduced LMWH bolus 2 h after the start of dialysis. All angiography patients received UFH at the start of the procedure, and 1 patient received 2 extra boluses of UFH. Serum PAPP-A concentrations were analyzed before and during the dialysis session and during the coronary angiography examination. RESULTS A rapid increase in total PAPP-A (median, 25-fold) was seen in all patients within 5 min of administration for both LMWH and UFH boluses. This response was due to an increase in free PAPP-A in the serum. PAPP-A did not increase significantly in the patients who underwent heparin-free hemodialysis. Repeated heparin boluses induced a new PAPP-A release. In vitro addition of heparins to samples of whole blood did not increase PAPP-A concentrations. CONCLUSIONS Intravenous administration of heparin induces an intense and rapid increase in free PAPP-A in the serum. We recommend that this effect be considered when PAPP-A is assessed as a biomarker in acute coronary syndromes.

Studies on the effects of heparin products on pregnancy-associated plasma protein A

BACKGROUND Intravenous low molecular weight (LMWH) and unfractionated heparin (UFH) increase the circulating concentrations of pregnancy-associated plasma protein A (PAPP-A), a novel cardiac risk marker, in haemodialysis and coronary angiography patients. METHODS To further investigate the mechanisms of heparin effects, free PAPP-A was analysed in serial serum samples collected during haemodialysis (intravenous LMWH), carotid endarterectomy or abdominal aortic aneurysm surgery (intravenous UFH), treatment at intensive care unit (subcutaneous LMWH), and coronary angiography (intravenous bivalirudin). PAPP-A was extracted from plaque tissue samples of endarterectomy and aneurysm patients. The interaction between heparin products and free PAPP-A was studied with gel filtration. RESULTS After intravenous UFH and LMWH free PAPP-A increased significantly but bivalirudin had no effect. After LMWH bolus in haemodialysis patients 85% of free PAPP-A was cleared with a half-life of 13.1 min and the rest with a half-life of 96.6 min. Subcutaneous LMWH led to lower and slower free PAPP-A elevation. PAPP-A extracted from plaque tissues was in free form and extraction was strongly enhanced by LMWH. Heparin products increased the molecular size of free PAPP-A. CONCLUSIONS The heparin-induced PAPP-A elevation is seen in various patients and should be taken into account when PAPP-A is studied as a biomarker.

Cystatin C as a predictor of all-cause mortality and myocardial infarction in patients with non-ST-elevation acute coronary syndrome

OBJECTIVES To investigate the predictive value of cystatin C among patients diagnosed with non-ST-elevation acute coronary syndrome (nSTE-ACS). DESIGN AND METHODS Admission serum samples from 245 nSTE-ACS patients were measured with a novel cystatin C immunoassay based on a dry-reagent, double monoclonal design. Creatinine concentrations, estimated glomerular filtration rates (eGFR) and one-year follow-up data were available for these patients. RESULTS During the follow-up period, 34 (14%) of patients had myocardial infarction (MI) and 25 (11%) died. Increased serum cystatin C was an independent predictor of all-cause mortality and combined events (all-cause mortality and MI) after adjustment to non-biomarker baseline factors, hazard ratio (HR) 2.19 (per increase of 1 tertile; 95% Cl 1.28-3.78, p=0.0046) and 1.75 (1.22-2.51, p=0.0024), respectively. Corresponding values for eGFR were 2.56 (1.43-4.59, p=0.0016) and 1.76 (1.23-2.53, p=0.0022), respectively. Creatinine was not an independent predictor of endpoints (p>0.05). CONCLUSIONS Cystatin C was associated with an increased risk of death and combined events in patients with nSTE-ACS.

Increased basal myocardial perfusion in patients with chronic kidney disease without symptomatic coronary artery disease

BACKGROUND Even minor renal dysfunction is a powerful cardiovascular risk factor. The abnormalities in coronary and peripheral artery function in different stages of chronic kidney disease (CKD) remain poorly understood. Our aim was to test by a positron emission tomography (PET)-based method whether microvascular dysfunction, an early marker of coronary dysfunction, exists already in early stages of CKD. METHODS Myocardial blood flow was measured at baseline and during dipyridamole-induced hyperaemia by PET. Peripheral artery endothelial function was examined by measuring flow-mediated dilatation (FMD) of the brachial artery at rest and during reactive hyperaemia. Twenty-two patients with moderate to severe kidney failure and 10 healthy controls were investigated. Diabetic patients were excluded. Baseline characteristics were similar between the groups with the exception of antihypertensive medication in all CKD patients. RESULTS The basal myocardial perfusion was statistically significantly higher in CKD patients than observed values in similarly aged controls. There was a statistically significant negative correlation between the baseline myocardial perfusion and the estimated glomerular filtration rate. Coronary flow reserve was comparable to healthy controls in all patients. FMD was significantly reduced in all patients with CKD regardless of the stage of kidney failure. CONCLUSIONS Coronary flow reserve was normal although baseline myocardial blood flow was increased in all CKD patients as compared to healthy controls. Peripheral endothelial dysfunction was detected in all patients. Our findings suggest that coronary perfusion and peripheral vascular function are disturbed by different mechanisms in patients with CKD.

Comparison of calcium phosphate product values using measurement of plasma total calcium and serum ionized calcium

Calcium phosphate product (Ca × Pi) is a clinically relevant tool to estimate the cardiovascular risk of patients with renal failure. In reports, mostly total serum calcium has been used. As measurement of serum ionized calcium has some benefits and is being used increasingly, we estimated the respective levels of calcium phosphate product using both total (t‐Ca × Pi) and ionized calcium (ion‐Ca × Pi). Fifty‐eight healthy individuals and 180 hemodialysis (HD) patients from 2 centers were studied. Diagnostic accuracies for corresponding values of the t‐Ca × Pi and ion‐Ca × Pi were calculated using a GraphROC program. Of HD patients, 64% had t‐Ca × Pi <4.4 mmol2/L2 regarded as a desirable goal, and 10% had values over 5.6 mmol2/L2 associated with a high cardiovascular risk. Based on GraphROC analysis, t‐Ca × Pi of 4.4 mmol2/L2 corresponded to a value of 2.2 mmol2/L2 of ion‐Ca × Pi and, respectively, t‐Ca × Pi of 5.6 mmol2/L2 corresponded 2.8 mmol2/L2 of ion‐Ca × Pi. Owing to the good agreement between the results in the 2 centers, these values for risk levels can be used in both centers. When measurement of ionized calcium is used, Ca × Pi values of 2.2 and 2.8 mmol2/L2 can be used instead of generally used values of 4.4 and 5.6 mmol2/L2 with total calcium.

The effect of revascularization of renal artery stenosis on renal perfusion in patients with atherosclerotic renovascular disease

BACKGROUND Only a small fraction of patients with atherosclerotic renovascular disease (ARVD) treated with revascularization have improved renal function after the procedure. It has been suggested that this may be due to effects of renal microvascular disease. Our aim was to measure the effect of renal artery stenosis (RAS) revascularization on renal perfusion in patients with renovascular disease. METHODS Seventeen renovascular disease patients were treated by dilatation of unilateral (N = 8) or bilateral (N = 9) RAS (N = 23 kidneys), mainly because of uncontrolled or refractory hypertension. The patients were studied before and after (103 ± 29 days) the procedure. Renal perfusion was measured using quantitative positron emission tomography (PET) perfusion imaging. RESULTS Although renal perfusion correlated inversely with the degree of RAS in patients with renovascular disease, it did not change after revascularization. CONCLUSIONS Our data support the notion of former clinical trials that angiographic severity of RAS does not determine the response to revascularization. Quantitative PET perfusion imaging is a promising tool to noninvasively measure renal perfusion for the assessment of physiological impact of RAS.

The Effect of Revascularization of Atherosclerotic Renal Artery Stenosis on Coronary Flow Reserve and Peripheral Endothelial Function

Background: Patients with atherosclerotic renovascular disease (ARVD) are at increased risk of heart disease because of associated hypertension, coronary artery disease, cardiac failure and chronic kidney disease. Although suggested to be beneficial, the cardiac effects of renal artery revascularization have not been well characterized. Our aim was to analyze the effects of percutaneous dilatation of renal artery stenosis (RAS) in ARVD patients on coronary and peripheral vascular function. Methods: Nineteen ARVD patients [11 females and 8 males, age at study entry (mean ± SD) 69 ± 10 years] were treated by dilatation of unilateral (n = 9) or bilateral (n = 10) RAS, mainly because of uncontrolled or refractory hypertension. The patients were studied before and after the procedure (103 ± 29 days). They underwent echocardiography and peripheral artery endothelial function testing using flow-mediated dilatation (FMD) of brachial artery at rest and during reactive hyperemia. Myocardial blood flow was measured using quantitative PET perfusion imaging at baseline and during dipyridamole-induced hyperemia. Results: Peripheral endothelial function, tested by FMD, as well as systolic blood pressure and left ventricular mass were improved in patients with bilateral RAS. However, myocardial perfusion and coronary flow reserve (CFR) did not change after the RAS dilatation. Conclusion: This is the first study to analyze the stage of myocardial perfusion and CFR in ARVD patients. Although peripheral endothelial function, systolic blood pressure and left ventricular hypertrophy were improved in patients with bilateral RAS by revascularization of RAS, it did not have any effect on coronary perfusion.

Passive immunization with monoclonal antibodies specific for lipopolysaccharide (LPS) O-side chain protects mice against intravenous Yersinia enterocolitica serotype O:3 infection

Passive immunization with monoclonal antibodies specific for the lipopolysaccharide (LPS) O‐side chain protected mice against intravenously given lethal doses of Yersinia enterocolitica O:3 bacteria. On the other hand, passive immunization with monoclonal antibody specific for the LPS core oligosaccharide did not protect mice. Neither antibody was able to protect mice against orally given lethal doses of bacteria. These results indicate that the O‐side chain functions as an important antigenic structure during infection, and that immunity to it probably offers protection also in the in vivo situation.

Thromboembolism as a Cause of Renal Artery Occlusion and Acute Kidney Injury: The Recovery of Kidney Function after Two Weeks

Thromboembolic occlusion is a rare cause of acute kidney injury (AKI). It may lead to permanent loss of renal function. Our patient, who had dilated cardiomyopathy and prosthetic aortic valve, presented with AKI due to thromboembolic arterial occlusion of a solitary functioning kidney. After 2 weeks delay, local intra-arterial thrombolytic treatment with recombinant tissue plasminogen activator was performed without sufficient effect. However, a subsequent percutaneous transluminal angioplasty with stenting was successful. Diuresis began immediately, and renal function was fully recovered after 2 weeks. Although there had been no evident arterial circulation in the kidney, we think that minor flow through subtotal occlusion of the main renal artery made the hibernation of kidney tissue possible and contributed to the recovery. Thus, even after prolonged ischemia, revascularization can be useful.

Elevated Serum Free Pregnancy-Associated Plasma Protein-A Independently Predicts Mortality in Haemodialysis Patients but Is Not Associated with Recurrent Haemodialysis-Induced Ischaemic Myocardial Injury

Background/Aims: Pregnancy-associated plasma protein-A (PAPP-A) is a putative marker of atheroma instability and ischaemic myocardial stress prior to necrosis. Total PAPP-A (tPAPP-A) levels in acute coronary syndromes predict adverse outcomes. However, free PAPP-A (fPAPP-A) predominates in the circulation. Ischaemic haemodialysis (HD)-induced cardiac injury (myocardial stunning) is common and is associated with markers of myocardial necrosis, inflammation, cardiovascular events and mortality. Coronary plaque instability in pathophysiology of HD-induced myocardial stunning has not been studied. We aimed to investigate the relationship of fPAPP-A with stunning and mortality. Methods: 130 prevalent patients from two HD centres (Finland and UK) were studied. Pre-HD free, complexed and total PAPP-A were measured by immunoassay. A subset of 62 patients underwent echocardiography to assess HD-induced myocardial stunning. The mean duration of follow-up was 407 ± 98 days. Results: fPAPP-A was elevated (median: 3.45 mIU/l) and correlated with dialysis vintage (r = 0.391, p < 0.001), cardiac troponin T (cTnT; r = 0.29, p = 0.001) and cardiac troponin I (cTnI; r = 0.22, p = 0.01). PAPP-A was not related to stunning. Dialysis vintage and cTnT independently predicted Ln fPAPP-A (model R = 0.463). fPAPP-A, cTnT and age independently predicted death (Nagelkerke R2 = 0.362). Conclusions: fPAPP-A, a novel predictor of HD-related mortality, demonstrates better prognostic power than tPAPP-A. Coronary plaque instability may contribute to sub-lethal myocardial injury, but may not be critical in pathogenesis of HD-induced ischaemic cardiac injury.