Viktor Persic

Obesity dilemma in the global burden of cardiovascular diseases

Obesity is a well‐known risk factor in the cardiovascular disease continuum. However, its clinical effects are multimodal, perplexed and non‐unanimously understood. Our aim was to assess the prevalence and effects of obesity on the cardiometabolic risk factors and systolic function of left ventricle ejection fraction (LVEF) in patients scheduled for cardiovascular rehabilitation.

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.

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.

Perforin‐Mediated Cytotoxicity in non‐ST Elevation Myocardial Infarction

The aim of this investigation was to examine the role of perforin (P)‐mediated cytotoxicity in the dynamics of tissue damage in patients with non‐ST‐segment elevation myocardial infarction (NSTEMI) treated with anti‐ischaemic drugs. We enrolled 48 patients with NSTEMI in this study [age, 71.5 years; 61.5/76 (median, 25th/75th percentiles)]. The percentage of total peripheral blood P+ lymphocytes was elevated owing to the increased frequency of P+ cells within natural killer (NK) subsets, T and NKT cells in patients on day 1 after NSTEMI when compared with healthy controls. Positive correlations were found between cardiac troponin I plasma concentrations and the frequency of P+ cells, P+ T cells, P+ NK cells and their CD56+dim and CD56+bright subsets during the first week after the NSTEMI. The expression of P in NK cells was accompanied by P‐mediated cytotoxicity against K‐562 targets at all days examined, except day 21, when an anti‐perforin monoclonal antibody did not completely abolish the killing. The percentage of P+ T cells, P+ NKT cells and P+ NK subsets was the highest on the day 1 after NSTEMI and decreased in the post‐infarction period. CD56+ lymphocytes were found in damaged myocardium, suggesting their tissue recruitment. In conclusion, patients with NSTEMI have a strong and prolonged P‐mediated systemic inflammatory reaction, which may sustain autoaggressive reactions towards myocardial tissue during the development of myocardial infarction.

Analysis of granulysin-mediated cytotoxicity in peripheral blood of patients with psoriatic arthritis.

The objective of the present study was to investigate possible changes in granulysin (GNLY)-mediated cytotoxicity of peripheral blood lymphocytes in psoriatic arthritis (PsA) patients with respect to different phases of the disease. We prospectively enrolled 25 PsA patients in the active phase, 26 PsA patients in remission and 24 healthy controls. The simultaneous detection of intracellular GNLY and cell surface antigens (CD3 and CD56) was performed with flow cytometry. GNLY apoptotic protein was visualised by immunocytochemistry. Natural killer (NK) cell cytotoxicity was analysed with a cytotoxicity assay against human erythroleukaemia K-562 cells. The percentage of GNLY+ cells did not differ significantly between PsA patients in the acute phase and those in remission; however, it was always higher than in healthy examinees due to the increased percentage of GNLY+ cells within T cells, NKT cells, and both, and in the CD56+dim and CD56+bright NK subsets. The mean fluorescence intensity for GNLY was higher in all lymphocyte subpopulations in the acute phase than in remission and in healthy controls. Accordingly, GNLY-mediated NK cell cytotoxicity against K-562 cells of active phase PsA patients was significantly higher than that in patients in remission or in healthy controls. These findings demonstrated the involvement of GNLY in the worsening of PsA and suggested that GNLY mediated the development of joint lesions.

Left ventricle diastolic dysfunction in obese patients with newly diagnosed arterial hypertension.

ZusammenfassungHINTERGRUND: Arterielle Hypertonie und Adipositas sind als unabhängige Risikofaktoren der linksventrikulären diastolischen Dysfunktion schon lange bekannt; ebenso bekannt ist die häufige Koexistenz von arterieller Hypertonie und Adipositas. Daten über die linksventrikuläre diastolische Dysfunktion bei adipösen Patienten mit neu diagnostizierter arterieller Hypertonie gibt es allerdings bisher nur wenige. Diese Studie wurde durchgeführt, um die Prävalenz der linksventrikulären diastolischen Dysfunktion bei adipösen Patienten mit neu diagnostizierter arterieller Hypertonie zu erheben. METHODEN: 125 adipöse Patienten wurden in unsere Studie einbezogen, davon 65 mit neu diagnostizierter arterieller Hypertonie. Alter, Geschlecht und Body Mass Index der Hypertoniker waren mit der Gruppe der 60 adipösen Nicht-Hypertoniker vergleichbar. Die linksventrikuläre diastolische Funktion wurde mittels Doppler-Echokardiographie durch Messung folgender Parameter erhoben: Geschwindigkeit des Mitral-Influx (E- und A-Welle), E-Wellen-Dezelerationszeit, isovolumetrische Relaxationszeit, linksatriale und linksventrikuläre Diameter, intraventrikuläre Septumdicke und linksventrikuläre Herzmasse. Ein E/A-Verhältnis <1 wurde als diastolische Dysfunktion aufgefasst. ERGEBNISSE: Bei neu diagnostizierten adipösen Hypertonikern wurden signifikant höhere A-Wellen, signifikant niedrigere E/A Verhältnisse, signifikant längere E-Wellen-Dezelerationszeiten und signifikant größere linke Vorhöfe gefunden. Die Spitzengeschwindigkeit der E-wellen unterschied sich nicht signifikant. Auch in der Prävalenz der linksventrikulären Hypertrophie und der linksventrikulären Herzmasse wurde kein signifikanter Unterschied gefunden. Die Prävalenz der diastolischen Dysfunktion war bei den adipösen Patienten mit neu diagnostizierter arterieller Hypertonie signifikant häufiger. KONKLUSION: Die Studie weist auf einen signifikanten Beitrag der neu diagnostizierten arteriellen Hypertonie zur Verschlechterung der diastolischen Funktion des linken Ventrikels bei adipösen Patienten – noch vor dem Nachweis struktureller Änderungen – hin.SummaryBACKGROUND: The frequent coexistence of obesity and arterial hypertension is well known. Although both conditions have been identified as independent risk factors for impaired left ventricular diastolic function, there is a paucity of data on the dysfunction among obese patients with newly diagnosed arterial hypertension. The study was performed to determine the prevalence of diastolic dysfunction in obese individuals with newly diagnosed arterial hypertension and to compare it with the prevalence in normotensive obese persons. METHODS: We enrolled 125 obese patients: 65 with newly diagnosed hypertension and 60 normotensive patients matched for age, sex and body mass index. Left ventricular diastolic function was assessed from the following Doppler-echocardiographic measurements: mitral inflow velocities (E and A wave), E wave deceleration time, isovolumetric relaxation time, left atrial and left ventricular diameters, left ventricular wall thickness and left ventricular heart mass index. Diastolic dysfunction was considered when the E/A ratio was <1. RESULTS: We found significantly higher A wave, lower E/A ratio, longer E deceleration time and a bigger left atrium in obese patients with newly diagnosed arterial hypertension. We did not find significant differences in E wave peak velocities between the two groups. Although there was no difference in left ventricle heart mass or the prevalence of left ventricle hypertrophy, the prevalence of diastolic dysfunction was higher in the group with newly diagnosed arterial hypertension. CONCLUSION: This study suggests that newly diagnosed arterial hypertension significantly contributes to impairment of left ventricular diastolic function in obese patients before development of structural aberrations detectable on echocardiography.

Influence of Transiently Increased Nutritional Risk on a Left Ventricle Myocardial Mass Assessed by Echocardiography

Background/Aim: Metabolic derangements due to increased nutritional risk lead to catabolism and loss of proteins, muscle tissue and eventually mass of parenchymatous organs. The aim of our study was to assess whether transitory nutritional risk after heart surgery influences on the left ventricle myocardial mass (LVMM), assessed by echocardiography. Methods: Consecutive sample of patients scheduled for cardiovascular rehabilitation, in period 0-3 months after surgery. Nutritional risk screening (NRS) was analyzed using the NRS-2002 tool. Results: Study sample included 330 patients after heart surgery for ischemic 186 (56.4%); valvular 91 (27.6%) and valvular plus ischemic 53 (16.1%) heart disease. Age was 65.5 ± 10.6 (range 23-84) and there were more male patients than female - 240 (72.7%) and 90 (27.3%), respectively. The percentage of unintentional loss of weight was 10.8 ± 3.4%, in range 0-23.81%, whereas NRS-2002 was 4.4 ± 1.1. LVMM was 218.7 ± 65.9 g vs. 252.3 ± 51.7 (p = 0.015); for patients with increased nutritional risk and controls, respectively. There was no significant correlation of LVMM with NRS-2002, while the percentage of unintentional loss of weight displayed only weakly inverse correlation (Rho CC = -0.197; p = 0.007). LVMM also correlated significantly with body mass index (Rho CC = 0.247; p < 0.001) and waist-to-hip ratio (Rho CC = 0.291; p < 0.001). In conclusion, LVMM was found to decrease slightly in the period of increased nutritional risk, following heart surgery. Changes in LVMM are partially consequences of systemic catabolic response, as well as anthropometric changes due to unintentional loss of weight.

Can pain intensity in osteoarthritis joint be indicator of the impairment of endothelial function

We propose that pathological remodeling in joint tissues of osteoarthritis (OA) patients persistently stimulates local secretion of pro-inflammatory mediators, which overflow into the blood, activating leukocytes that impair endothelial function and accelerate the atherosclerotic process. During periods of pain, endothelial dysfunction progresses more aggressively due to elevated secretion of these pro-inflammatory mediators, which are involved in both atherosclerosis and the sensation of pain. Concentrations of pro-inflammatory cytokines and their antagonists, activating and decoy receptors of the broad interleukin (IL)-1 and IL-17 families, IL-15, and monocyte chemotactic protein-1 should be measured in peripheral blood samples of OA patients and compared with (I) OA clinical severity; (II) subclinical parameters of atherosclerosis; (III) ischemic heart disease risk factors; (IV) soluble factors indicating endothelial dysfunction; (V) degree of bone destruction; and (VI) results of a six-minute walk test. Arthroscopy and joint replacement surgery provide an opportunity to estimate mRNA and protein expression of inflammatory mediators in specimens of synovial fluid, synovial membrane, cartilage, and/or subarticular bone. A range of methods, including questionnaires, X-ray, computed tomography, ultrasound, enzyme-linked immunosorbent assay, immunohistology, immunofluorescence, and reverse transcription and in situ polymerase chain reaction are available. Understanding the inflammatory and immune mechanisms underlying OA may allow the early identification of patients at high risk of cardiovascular disease, independently of classical coronary risk factors. Pain may constitute an extrinsic indicator of currently worsening endothelial function.

Heart surgery stems increased nutritional risk, expressed during the course of stationary rehabilitation.

Background: Cardiovascular diseases are a vast global health burden. Despite common prevalence, current knowledge and investigations concerning nutritional aspects are limited. Characteristics and dynamics of nutritional risk are not entirely known for most of the entities, disease stages or treatment-induced fluctuations. This study assessed the effects of heart surgery on unintentional weight loss and nutritional risk using the NRS-2002. Methods: A noninterventional study that included patients scheduled for rehabilitation 1-6 months after heart surgery was performed. Evaluation included routine cardiovascular diagnostics and review of medical histories. Documented baseline weight was available for >85% of the patients. Nutritional risk screening was performed with the standardized NRS-2002 questionnaire. Results: A total of 145 patients were involved, with a mean age of 65.3 ± 11.5 years in a range of 23-84 years. The male to female ratio was 121:24 (83.4%:16.6%), respectively. Coronary artery bypass graft surgery (CABG) was performed in 89 patients (61.4%), valvular surgery (VS) in 34 (23.4%) and combined operations (CABG + VS) in 22 (15.2%). Percentage weight loss history was 11.1 ± 3.4% in a range of 0-20.1%, while NRS-2002 was 4.77 ± 1.05 in a range of 1-6. Increased nutritional risk (NRS-2002 ≥3) was found in nearly all patients. Combined ischemic and valvular etiology displayed the highest values of NRS-2002 (5.0 ± 1.2). Patient age and creatinine showed significant correlations with NRS-2002 (Rho = 0.521, p < 0.001 and Rho = 0.335, p < 0.001, respectively). Conclusion: Increased nutritional risk was found to be frequently prevalent in patients scheduled for rehabilitation after heart surgery. Risk was found to be in relation with underlying coronary artery disease as well as with the age of patients and parameters of renal function. Routine application of nutritional risk screening appears to be a valuable clinical tool for detecting this relevant comorbidity, particularly since no connection was found with traditional anthropometrics.

Prolonged utilization of proton pump inhibitors in patients with ischemic and valvular heart disease is associated with surgical treatments, weight loss and aggravates anemia

BACKGROUND Proton pump inhibitors (PPIs) are among the commonest drugs used nowadays. The aim of our study was to analyze prolonged utilization of proton pump inhibitors in medical therapy of patients with ischemic and valvular heart disease. Secondly, profile of utilization was scrutinized to patient characteristics and type of cardiovascular treatments. METHODS The study included consecutive patients scheduled for cardiovascular rehabilitation 2-6months after index cardiovascular treatment. RESULTS Two hundred ninety-four patients (n=294/604; 48.7%) have been using proton pump inhibitor in their therapy after index cardiovascular treatment. Cardiovascular treatments were powerfully connected with utilization of PPIs; surgery 5.77 (95%-confidence intervals [CI]: 4.05-8.22; p<0.001) and PCI 0.15 (CI: 0.10-0.22; p<0.001). The odds for having proton pump inhibitor in their chronic therapy were increased for atrial fibrillation 1.87 (CI: 1.08-3.23; p=0.025) and decreased for obesity 0.65 (CI: 0.45-0.96; p=0.035); surviving myocardial infarction 0.49 (CI: 0.29-0.83; p=0.035). Multinomial logistic regression controlled for existence of chronic renal disease found no significant association of renal dysfunction and PPI therapy. The existence of anemia was significantly increased in patients taking PPIs than controls; 6.00 (CI: 3.85-9.33; p<0.001). The use of PPI was also associated with worsening of metabolic profile, in part due to decreased utilization of ACE-inhibitors and statins. PPI consumption correlated with age of patients (Rho=0.216; p<0.001). CONCLUSIONS High proportion of cardiovascular, particularly surgical patients with ischemic and valvular heart disease utilized proton pump inhibitor in prolonged courses. Prolonged courses of PPIs were connected with existence and worsening of red blood count indexes, older age, lesser weight of patients and underutilization of cardioprotective drugs.