Is there a relationship between hypomagnesemia and proton-pump inhibitors in patients on chronic hemodialysis?

AIM: We investigated the association among long-term proton-pump inhibitors (PPIs) use with serum magnesium (Mg) levels in chronic hemodialysis (HD) patients, as well as possible association among PPI use and increased risk of cardiovascular (CVD) morbidity in HD patients. METHODS: Of 418 HD patients that were screened for inclusion, 136 were excluded due to incomplete medical data, duration of renal replacement therapy (RRT) for less than 12months, use of Mg-based-phosphate binders or other Mg-based medications or either to presence of chronic increased GI losses. Among 282 patients included in the study, 170 patients were on PPIs. RESULTS: Serum Mg levels were significantly lower among PPI users vs. non-users (0.94±0.2 vs. 1.03±0.2mmol/L; p<0.0001). The median duration of PPI use was 27±9.6months (range from 12 to 108) and it was not significantly associated with Mg levels (r=0.116; p=0.167). Additionally, residual renal function didn't show a significant correlation with Mg concentration (r=-0.102; p=NS) in both groups of patients. The use of PPIs was an independent and strong predictor of low Mg concentrations even in multivariate analysis (OR 3.05; 95% CI 1.2498-7.4594, p=0.01). On the other hand, the daily dose of PPIs was not associated with low Mg levels. PPI users had a higher rate of adverse CVD events during the 1 year of follow-up in comparison to non-PPI users but that difference wasn't statistically significant (17.6% vs. 10.7%; p=0.110). CONCLUSION: We have found a significant association between PPI use and lower serum Mg levels in chronic HD patients.

Renin-angiotensin-aldosterone system inhibitors lower hemoglobin and hematocrit only in renal transplant recipients with initially higher levels.

AIM: We have analyzed the effects of renin-angiotensin-aldosterone system (RAAS) inhibitors on evolution of hemoglobin (Hb) and hematocrit (Htc) levels as well as on the evaluation of kidney graft function in stable renal transplant recipients (RTRs) in respect with initially higher or lower Hb and Htc values. METHODS: The study group comprised of 270 RTRs with stable graft function. Besides other prescribed antihypertensive therapy, 169 of them have been taking RAAS inhibitors. RESULTS: We wanted to analyze the effect of the use of RAAS inhibitors on Hb and Htc in patients with initially higher or lower Hb/Htc values. For this analysis, only RTRs that were taking RAAS inhibitors were stratified into two groups: one with higher Hb and Htc (initial Hb≥150g/L and Htc≥45%) and another one with lower Hb and Htc (initial Hb<150g/L and Htc<45%) values. Thirty-four RTRs with initially higher Hb and 41 RTRs with initially higher Htc had a statistically significant decrease in Hb (p=0.006) and Htc (p<0.0001) levels after 12-months of follow-up. In the group of patients with initially lower Hb (135 RTRs) and Htc (128 RTRs) there was a significant increase in Hb (p=0.0001) and Htc (p=0.004) levels through the observed period. The use of RAAS inhibitors has been associated with a trend of slowing renal insufficiency in RTRs (p=0.03). CONCLUSION: RAAS inhibitors lower Hb and Htc only in RTRs with initially higher levels. In patients with initially lower Hb and Htc levels, the use of these drugs is followed by beneficial impact on erythropoiesis and kidney graft function.

Nonalcoholic fatty liver disease (NAFLD): a new risk factor for adverse cardiovascular events in dialysis patients.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in Western countries. Today it is believed that NAFLD is a hepatic manifestation of metabolic syndrome, and thus it is closely related to the cardiovascular morbidity and mortality. Cardiovascular diseases (CVD) are the leading cause of morbidity and mortality in patients with end-stage-renal disease (ESRD). NAFLD and ESRD share some important cardiometabolic risk factors and possible common pathophyisiological mechanisms, and are linked to an increased risk of incident CVD events. We hypothesize that the coexistence of these two conditions could lead to much faster progress of the aterogenic process. Furthermore, patients with ESRD who suffer from NAFLD have a much higher risk for the development of adverse CVD events. Given the high prevalence of NAFLD, and its tight association with other manifestations of the metabolic syndrome and thus cardiovascular complications, it is important to recognize and aggressively treat this condition in ESRD patients. To evaluate this hypothesis, we propose the use of non-invasive methods such as transient elastography (TE) (Fibroscan-CAP) for the detection and quantification of liver steatosis and fibrosis, as well as an abdominal ultrasound for detecting liver steatosis. We focus on their correlation with carotid intima-media thickness (IMT) and plaque as surrogate measures of increased cardiovascular risk in HD patients in order to investigate the association of NAFLD and increase risk of adverse CVD events. This evaluation will prove useful in assessing the risk in HD patients with NAFLD for increase CVD mortality.

Can we assess an acute myocardial infarction in patients with acute coronary syndrome according to diagnostic accuracy of heat shock proteins?

Heat shock proteins (HSPs) have changed very little with evolution, suggesting that they play important role(s) in cellular survival. Specifically, HSPs protect cells from induced cell death. Their expression is triggered by heat or other stress, such as ischemia. HSPs provide protection against protein denaturation, although they slightly differ with respect to group affiliation. Release of HSPs from necrotic and ischemic cardiomyocytes into the intercellular space and plasma may correlate with the intensity of the pro-inflammatory response observed during and immediately after myocardial infarction. We hypothesized that the plasma concentration of particularly inducible forms of HSPs from different groups (HSP 90, HSP 70, HSP 60 and/or HSP 20) can be used as early specific markers for diagnosing myocardial infarction in patients with acute coronary syndrome. Our hypothesis is supported by the following data: (I) HSP expression occurs very early after acute coronary events; (II) HSP concentrations increase rapidly in the peripheral blood; (III) HSP concentrations correlate with markers of myocardial necrosis and pro-inflammatory biochemical parameters. The magnitude of the increase in plasma HSP concentrations over initial concentrations during the period of highest sensitivity and specificity of the assay could be important for early detection of myocardial infarction and distinguishing it from unstable angina. We suggest that these parameters, along with close observation of patients with chest pain, will assist providers who must differentiate between acute myocardial damage and other organ diseases.

Harmful immune reactions during acute myocardial infarction.

Acute coronary syndrome, including myocardial infarction, can occur as a result of ischaemia-reperfusion injury caused by acute occlusion of the coronary vessel/s following the rupture of an atherosclerotic plaque. Superimposed thrombosis at the lesion obstructs blood supply to the myocardium causing myocardial necrosis and ischaemic inflammation. Although not fully described, researchers believe that this process is initiated by a dysfunctional endothelium that activates the nearby leukocytes in the blood stream, thus attracting them to the arterial wall and initiating a cascade of complex mechanisms that lead to myocardial infarction. Interestingly, this process is two sided as the leaking soluble factors from a damaged and/or necrotic myocardium enter the systemic circulation, activating the innate and adaptive cell-mediated immune responses, which include increasing cytotoxic mediators. We hypothesize that this unwanted side effect of increase in proinflammatory mediators can lead to harmful systemic immune reactions directed towards various dysfunctional endothelia. Additionally, a strong inflammatory response, caused by myocardial damage, can impair ventricular function, on top of baseline necrosis. To evaluate this hypothesis, we propose to use in vivo tests to measure endothelial dysfunction, as well as ventricular dysfunction by ultrasound methods, and their correlation with immunological and/or biochemical parameters. These tests will be useful in assessing the risk and therapeutic outcome in patients with acute coronary syndrome.

Granulysin Expression in Lymphocytes that Populate the Peripheral Blood and the Myocardium after an Acute Coronary Event.

We aimed to analyse granulysin (GNLY)-mediated cytotoxicity in the peripheral blood of patients with non-ST-segment elevation myocardial infarction (NSTEMI) treated with anti-ischaemic drug therapy. Thirty-nine NSTEMI patients with a median age of 70 years and 28 age-matched healthy subjects were enrolled in this study. On day 7 after MI, the number of GNLY(+) lymphocytes in the peripheral blood increased approximately six-fold of that in the healthy subjects, measured by flow cytometry. On day 14, the number of GNLY(+) cells significantly decreased in T, NKT, and both CD56(+dim) and CD56(+bright) NK subsets. GNLY(+) CD3(+) and GNLY(+) CD56(+) cells infiltrated central zone of myocardial infarction (MI). In persons who died in the first week after MI, GNLY(+) cells were found within accumulation of apoptotic leucocytes and reached the apoptotic cardiomyocytes in border MI zones probably due to the influence of interleukin-15 in peri-necrotic cardiomyocytes, as it is was shown by immunohistology. By day 28, the percentage of GNLY(+) lymphocytes in peripheral blood returned to the levels similar to that of the healthy subjects. Anti-GNLY mAb decreased apoptosis of K562 targets using peripheral blood NK cells from days 7 and 28 after MI, while in assays using cells from days 1 and 21, both anti-GNLY and anti-perforin mAbs were required to significantly decrease apoptosis. Using NK cells from day 14, K562 apoptosis was nearly absent. In conclusion, it seems that GNLY(+) lymphocytes, probably attracted by IL-15, not only participate partially in myocardial cell apoptosis, but also hasten resolution of cardiac leucocyte infiltration in patients with NSTEMI.

Apoptotic cell death and rupture of abdominal aortic aneurysm.

The abdominal aortic aneurysm (AAA) development and expansion is characterized by an extracellular matrix degradation and widespread inflammation. In contrast, the processes that characterize the AAA rupture are not completely understood. The results obtained in animal and clinical studies have shown the importance of inflammation, proteolysis, and antioxidant mechanisms in the aortic degeneration and formation of AAA. We hypothesize that the rupture of the AAA could have a similar pathway like an atherosclerotic plaque rupture, and in both the cases the apoptotic cell death of smooth muscle cells could play a significant role. If the apoptotic cell death significantly contributes to the expansion and rupture of aneurysm, the hypothesis is that aggressive medical antiapoptotic treatment with high doses of appropriate drugs could decrease the apoptotic index of smooth muscle cells, reduce the aneurysm expansion and prevent rupture.

Interferon-gamma receptor-1 gene promoter polymorphisms (G-611A; T-56C) and susceptibility to tuberculosis.

We analysed frequencies of two single-nucleotide polymorphisms (SNP) in the interferon-gamma (IFN-gamma) receptor-1 (IFNGR1) gene promoter (G-611A, T-56C) in tuberculosis patients (n = 244) and compared them with controls (n = 521). These frequencies were not significantly different, whether analysed independently or as haplotypes. Because these SNP affect transcription, the results suggest that the expression of the IFNGR1 gene does not confer susceptibility to disease in patients from Croatia. Further analysis revealed a significant association between the protective (CA)(n) polymorphism (22 repeats, 192 FA(1)), located in the fifth intron of the IFNGR1 gene (+16682), and GT promoter haplotype (-611; -56) that showed the strongest expression capacity. In addition to this cis relationship, the (CA)(22) allele was correlated in trans with an IFN-gamma SNP (IFNG G + 2109A), which might affect the transcription of the IFNG gene. These results suggest that a particular combination of IFNG and IFNGR1 SNP might offer a better protection against tuberculosis in this population.

Eligibility of patients with acute myocardial infarction for thrombolytic therapy: retrospective cohort study.

AIM: To investigate the eligibility of patients with acute myocardial infarction (AMI) for thrombolytic therapy (TT) and evaluate the results of treatment. METHODS: Retrospective analysis included 366 patients with AMI, mean age 66+/-11 years, treated in 1999. We analyzed age, gender, previous infarction, previous TT, present TT with streptokinase and its effects on the course and outcome, pain-to-door time, and door-to-needle time. Reperfusion and reocclusion were evaluated non-invasively according to the occurrence of the reperfusion and reocclusion syndrome. RESULTS: One hundred patients (27%) underwent TT. It was less frequently applied in older patients, women, and patients with previous myocardial infarction. Reperfusion was achieved in 66 (66%) patients and reocclusion occurred in 9 (14%). Final outcome was successful in 57 (57%) patients. The TT group had more frequent arrhythmias (67% vs. 41%, p<0.001) and less frequent heart failure (20% vs. 39%, p<0.001) than the patients without TT. The mortality after TT was significantly lower (7% vs. 17%, p=0.015), without fatal outcome in patients with finally successful TT. Reasons against TT application were late arrival to hospital (51%) and contraindications for TT (34%). In patients without TT, the median pain-to-door time and door-to-needle time were significantly longer than in the TT group (7 vs. 2.5 hours and 55 vs. 20 min, respectively; p<0.001). CONCLUSION: Older age, female gender, previous myocardial infarction, and late arrival to the CCU negatively influence the use of TT in AMI. TT should be improved by shortening pain-to-door time, broadening indications, and limiting contraindications.

Unmasking effect of propafenone on the concealed form of the Brugada phenomenon.

A case report of a patient with frequent ventricular premature beats but with an otherwise normal ECG and no structural heart disease. Propafenone in therapeutical doses unmasked the ECG picture of the Brugada phenomenon.

Relationship between QT dispersion and the incidence of early ventricular arrhythmias in patients with acute myocardial infarction.

There is controversy about the influence of QT dispersion on the incidence of early ventricular arrhythmias in patients with acute myocardial infarction (AMI). The QT and QTc dispersion (QTd, QTcd) between two groups of patients with AMI were compared: 39 patients with early sustained ventricular tachycardia or ventricular fibrillation (VT/VF) and 40 patients without such arrhythmias. QTd and QTcd were calculated from the admission and predischarge ECG, expressed as the difference between the maximum and minimum QT and QTc interval in 12 leads. The coefficient of variability was also calculated (VQT, VQTc). Groups did not differ significantly in age, incidence of previous infarction, Killip class, electrolyte status, infarct location, expected and final ECG infarct size, enzymatic infarct size, thrombolytic treatment and reperfusion rate, i.e., in variables that could influence the VT/VF occurrence. On admission, patients with VT/VF had significantly greater QTd (77+/-23 vs 53+/-27 ms, P<0.001) and QTcd (90+/-29 vs 62+/-28 ms, P<0.001); VQT and VQTc were also significantly higher. Although similar differences existed on predischarge ECG, they were smaller. The results indicate that QT dispersion varies during the illness, and that measurements of QT dispersion could be helpful in predicting serious ventricular arrhythmias.

Usefulness of blood lactate as a predictor of shock development in acute myocardial infarction.

Data were obtained and analyzed in 229 patients admitted to the coronary care unit from November 1988 through July 1989. The patients were classified into 2 groups: patients without or with only mild left ventricular failure (Killip class I or II) during their hospital stay (group I), and patients who were in Killip class I or II on admission but developed cardiogenic shock during hospitalization (group II). Discriminant function analysis was performed using the following variables: patients' age, history of previous myocardial infarction, diabetes mellitus, blood lactate, urea, creatinine, creatine kinase, aspartate aminotransferase, lactate dehydrogenase concentrations, and chest x-ray cardiothoracic ratio. Variables that were found to significantly discriminate the 2 groups of patients were age, previous infarction, x-ray cardiothoracic ratio, blood urea and lactate concentrations. The risk index was computed, and blood lactate was the variable with the greatest predictive power for shock development. The sensitivity, specificity and predictive value of the risk index, taking various cutoff points, were calculated. With a cutoff value of 1, sensitivity was 65%, specificity 91%, positive predictive value 36% and negative predictive value 97%. With a cutoff value of 2, sensitivity was 53%, specificity 99%, positive predictive value 82% and negative predictive value 96%.

Prognostic significance of complete atrioventricular block in patients with acute inferior myocardial infarction with and without right ventricular involvement.

Data were obtained and analyzed in 243 patients with acute inferior myocardial infarction who were admitted to the coronary care unit during the years 1987 and 1988. One hundred and ninety-eight patients had no signs of right ventricular involvement (group I), whereas 45 patients had inferior myocardial infarction with right ventricular infarction (group II). Patients were divided into groups depending on the presence or absence of complete atrioventricular block during hospital stay (groups Ia and IIa without block and groups Ib and IIb with block). Selected clinical and laboratory variables were compared for each group. We found that patients with inferior myocardial infarction and complete atrioventricular block had significantly higher mortality rates only in the presence of right ventricular infarction: 41% mortality rate in group IIb versus 11% mortality rate in group Ib (p less than 0.05). Patients with right ventricular infarction but without complete atrioventricular block (group IIa) had a mortality rate similar to that found in patients with inferior myocardial infarction and no atrioventricular block (group Ia): 14% versus 11% (p = NS). In patients with inferior myocardial infarction without right ventricular involvement (group I), complete atrioventricular block did not influence survival: 14% mortality rate in group Ib versus 11% mortality rate in group Ia (p = NS). The excessively high mortality rate in patients who have inferior myocardial infarction with right ventricular involvement and complete atrioventricular block could be the consequence of greater infarct size, but the synergistic influence of right ventricular infarction and complete atrioventricular block could be the other factor that influences outcome.

Lymphocyte subpopulations in the blood and cerebrospinal fluid of multiple sclerosis patients in active disease.

Lymphocyte subpopulations (total T cells, active T cells and B cells) were simultaneously analyzed in peripheral blood and CSF of MS patients. All patients were in active disease, 3 to 4 weeks after first signs of disease activation appeared. Per cent levels and absolute numbers of examined lymphocyte subpopulations in the blood of MS patients were significantly lower than in healthy controls. In MS, the level of active T lymphocytes was lower in CSF than in peripheral blood. The results support our earlier observations relating to the role of active T lymphocytes in the clinical course of disease.