Michał Zakliczyński

Advanced glycation end product accumulation in the cardiomyocytes of heart failure patients with and without diabetes.

BACKGROUND Non-enzymatic coupling of protein and lipid cellular structures with glucose leading to the formation of advanced glycation end products (AGE) plays a role in aging and the development of diabetic complications, but its contribution to myocardial pathology is unclear. We aimed to assess the role of heart failure on AGE formation in patients with or without diabetes mellitus type 2 (DM2). MATERIAL/METHODS Heart tissue specimens from 136 patients undergoing transplantation were grouped as follows: 14 cases of ischemic cardiomyopathy (ICM) and DM2, 8 cases of dilated cardiomyopathy (DCM) and DM2, 67 cases of ICM without DM2, and 47 cases of DCM without DM2. Fourteen heart samples were from the autopsies of patients with DM2 without heart disease, and 20 heart samples were from organ donors in whom the heart was wasted. AGE deposits were localized immunohistochemically counted using a semiquantitative scale and characterized by their staining pattern. RESULTS Positive staining was present in all samples from both cardiomyopathy groups with DM2, in 71% of healthy hearts from the DM2 subjects, in 51% of ICM non-diabetic hearts, and in 38% of DCM non-diabetic hearts, and in only 15% of the organ donors. Mixed-diffuse and granular AGE patterns were characteristic for DM2, while a diffuse pattern was more frequently observed in heart failure patients without diabetes. The semiquantitative results supported increased AGE accumulation in patients with DM2 and/or cardiomyopathy. CONCLUSIONS The amount of AGE in cardiomyocytes increases significantly in both diabetes and heart failure, with a staining pattern typical for each condition.

In the era of the universal use of statins dyslipidemia's are still common in heart transplant recipients: a cross-sectional study.

BACKGROUND Statins are used in orthotopic heart transplant (OHT) recipients to avoid acute rejection episodes (ARE) during the first year after surgery and coronary vasculopathy (CAV) thereafter as established in prospective randomized trials, yielding the grounds for the universal use of this group of drugs. The aim of the study was to describe the occurrence of dyslipidemias among OHT recipients after introduction of guidelines suggesting the use of statins in all individuals able to tolerate this therapy. METHODS Medical records of all OHT recipients undergoing routine clinical checkups between January and June 2010 were screened for the presence of dyslipidemia: total cholesterol>5 mmol/L; low-density lipoprotein (LDL)-cholesterol>3 mmol/L; triglycerides>1.65 mmol/L; high-density lipoprotein (HDL)<1 mmol/L in the serum. The study group consisted of 322 subjects including 265 males and 57 females of overall mean age of 53.6±12 and 7±4 years after OHT. There was coronary artery disease (CAD) before OHT in 113 (35%). The average number of ARE was 1.9±1.9 and CAV was diagnosed in 77 (24%) patients. There were 247 (77%) patients on statins. We analyzed clinical, ultrasound, and biochemical evaluations to characterize subjects with dyslipidemias. RESULTS At least one dyslipidemia was observed among 212 (66%) including hypercholesterolemia in 121 (38%), high LDL in 135 (42%), hypertriglyceridemia in 110 (34%), and low HDL in 48 (15%) patients. The subjects with dyslipidemia were prone to be older, to have CAD before OHT, and to be hypertensive, overweight, and obese, as well as display an higher HbA1C when diabetic. They were treated less frequently with tacrolimus but showed higher drug levels, and more often were prescribed everolimus. CONCLUSIONS Despite almost universal use of statins, dyslipidemias were present in 2/3 of OHT recipients. It was related to typical atherosclerotic risk factors; however, the influence of immunosuppressants seemed to also be significant.

The Influence of Chronic Heart Failure on Pulmonary Function Tests in Patients Undergoing Orthotopic Heart Transplantation

BACKGROUND Chronic heart failure and airway obstruction produce overlapping syndromes. Existent criteria for the diagnosis and grading of airway obstruction based on spirometry results may be inadequate in the presence of coexistent cardiac failure. The cardiac component of pulmonary function tests (PFT) can be measured in patients undergoing orthotopic heart transplantation (OHT). MATERIALS AND METHODS Before and 1 year after OHT between 2006 and 2008 PFT were performed in 29 patients according to existent guideline. Willcoxon matched pair tests were used for analysis in Statistica 7.1. The general group characteristic included age, gender, New York Heart Association class, CCS class, body mass index, present medications, blood and chemistry tests, as well as exercise tolerance tests, right heart catheterization, and echocardiography results. RESULTS One year after OHT we observed significant improvements in forced expiratory volume in the first second (FEV1) and its percent of normal value (FEV1%) as well as forced vital capacity (FVC), FVC%, vital capacity (VC) and VC%: namely, 2.56 L versus 2.96 L; 82% versus 93%; 3.30 L versus 3.81 L; 85% versus 97%; 3.38 L versus 4.04 L and 85% versus 100% (all P < .01). FEV1 and FVC increments of: 0.39 and 0.471 respectively, exceeded the cutoff point of 12% of predicted value established as the spirometry criterion for reversibility of obstruction. Elimination of heart failure by OHT did not significantly change the FEV1 to FVC ratio (FEV1%FVC). CONCLUSION Chronic heart failure contributed to significant FEV1 reduction, which limits the usefulness of PFT for diagnosis and grading of airway obstruction. FEV1%FVC, the main diagnostic criterion of chronic obstructive lung disease, seems to be an index independent of concomittant heart function impairment.

Advanced glycation end-products in myocardium-supported vessels: Effects of heart failure and diabetes mellitus

BACKGROUND Disturbed glucose metabolism, particularly in diabetes, is an important but not the sole factor leading to advanced glycation end-product (AGE) formation. The AGE amount and its distribution in cardiopathic myocardial tissues in the presence or absence of diabetes are not well documented. The aim of this study was to assess AGE deposition in unaffected myocardial vessels in heart failure patients with and without diabetes mellitus type 2 (DM2) undergoing transplantation. METHODS The following groups were established: 14 hearts harvested from subjects with ischemic cardiopathy and DM2; 8 hearts from subjects with dilated cardiopathy with DM2; 67 hearts from subjects with ischemic cardiopathy; 47 hearts from subjects with dilated cardiopathy; and 14 hearts from autopsy cases with diagnosed DM2. A control group consisted of 20 heart donors. AGE localization was determined immunohistochemically in tissue sections. A semi-quantitative scale was used to assess reaction intensity in arteries, arterioles, capillaries, venules and veins. RESULTS Both types of cardiomyopathy increased AGE accumulation in intramyocardial veins more than in arteries. The presence of DM2 significantly increased AGE in arterioles and capillaries, especially when coexisting with cardiomyopathy. The type of cardiopathy did not influence the pattern of AGE accumulation in myocardial vessels. CONCLUSION Both chronic heart failure and DM2 intensified AGE pathology and changed the susceptibility of myocardial vasculature to glycation. However, chronic heart failure increases AGE deposition mostly in veins, whereas DM2 predisposes arterioles to AGE accumulation.

Advanced Glycation End Products in the Development of Ischemic and Dilated Cardiomyopathy in Patients With Diabetes Mellitus Type 2

INTRODUCTION Hyperglycemia intensifies nonenzymatic glucose coupling to tissues, resulting in myocardial stiffness and formation of advanced glycation end products (AGE). The aim of this study was to assess seeking AGE in the myocardium from patients with type 2 diabetes (DM2) subjected to orthotopic heart transplantation (OHT), seeking to establish whether AGE play a role in the development of cardiomyopathies leading to OHT. MATERIAL The 2 studied groups consisted of 11 hearts explanted from patients with ischemic cardiomyopathy+DM2 (ICM+DM2, 55 +/- 6.5 years) and 8 from dilated cardiomyopathy+DM2 (DCM+DM2, 49.6 +/- 4.5 years). Comparative subgroups were composed of nondiabetic explanted hearts, 41 with ICM (52.8 +/- 5.8 years) and 41 with DCM (52.7 +/- 4.2 years). All patients were males. METHODS We examined immunohistochemical localization of AGE using a semiquantitative scale of reaction intensity in cardiomyocytes, fibroblasts, capillaries, arterioles, and arteries. Additionally, we calculated the scores for cardiocytes (AGE(Cardiocyte)) and all left ventricular components (AGE(LV)). RESULTS The cytoplasmic AGE deposits in cardiomyocytes were predominantly diffuse-granular in DM2 groups, whereas nondiabetic groups showed a lack of a reaction or a diffuse pattern. There were no differences in the reaction intensity between the 2 studied groups, or 2 comparative groups. All myocardial constituents showed higher AGE intensity in DM2 than nondiabetic groups. Only in the ICM+DM2 group did the DM2 duration correlate with AGE staining in selected myocardial layers and with AGE(Cardiocyte) and AGE(LV). CONCLUSIONS The presence of AGE in the hearts of patients requiring transplantation was related to the duration of DM2. The deposition of AGE in left ventricular myocardium was enhanced by DM2 particularly in patients with ICM.

Cytomegalovirus Infection Does Not Accelerate Microvasculopathy Development in Heart Transplant Recipients

BACKGROUND Clinical studies with intravascular ultrasound have suggested that even subclinical cytomegalovirus (CMV) infections increase intimal hyperplasia in transplanted heart coronary arteries after 1 year. The potential influence of CMV on microvasculopathy development is not known. The Aim of our study was to compare the occurrence of microvasulopathy in endomyocardial biopsies (EMBs) of heart transplant recipients with versus without CMV infection. MATERIALS AND METHODS We performed a case-controlled, retrospective study of 58 subjects diagnosed with CMV infection by the presence of pp65 antigen. The 49 men and 91 women of overall age 49 +/- 8 years showed ischemic cardiomyopathy in 52%. We matched a control cohort of 58 subjects without CMV disease. Microvasculopathy was assessed using 4-degree grading system developed by Hiemann et al for elective EMBs performed at 1 and 12 months after transplantation. RESULTS Significant acute rejection episodes were observed among 22% versus 21% of 1-month EMBs, and 3% versus 5% of 12-month EMBs for CMV(+) versus control group subjects respectively. The commonest microvasculopathy was nonstenotic thickening (grade B) 60% versus 59% (35 versus 34 patients) among 1-month EMBs; and 50% versus 60% (29 vs 35 patients) among 12-month EMBs, respectively. Progression of microvasculopathy score between 1- and 12-month EMB was observed in 40% versus 41% of subjects, and regression occurred in 22% versus 21%, respectively. None of differences was significant. CONCLUSION Our data do not support the thesis that CMV infection promotes microvasculopathy development among heart transplant recipients.

Heart Rate Turbulence for Prediction of Heart Transplantation and Mortality in Chronic Heart Failure

Background: Previous studies have shown conflicting results about the value of heart rate turbulence (HRT) for risk stratification of patients (pts) with chronic heart failure (CHF). We prospectively evaluated the relation between HRT and progression toward end‐stage heart failure or all‐cause mortality in patients with CHF.

Serum leptin concentration in patients after heart transplantation.

Abstract:  Leptin is primarily produced by adipocytes but its receptors are expressed in a variety of tissues including the heart. Elevated plasma leptin levels predict acute myocardial infarction and it has been shown as acute phase reactant and a risk factor for coronary heart disease. The present study was undertaken to answer the question whether there exists a relationship or not, between serum leptin levels and grades of acute cellular rejection confirmed by elective endomyocardial biopsies in stable patients after orthotopic heart transplantation. We observed higher serum leptin levels compared with reference values, regardless of histopathologic biopsy findings studied. There was a positive correlation between serum leptin concentrations and body mass index, diastolic blood pressure, total cholesterol and low‐density lipoprotein. The elevated leptin levels found in heart transplant recipients could be due to the result of steroid therapy. These results point the need for further studies to explain the leptin role in heart transplant recipients.

Von Willebrand factor in patients on mechanical circulatory support - a double-edged sword between bleeding and thrombosis.

Mechanical circulatory support (MCS) is an umbrella term describing the various technologies used in both short- and long-term management of patients with either end-stage chronic heart failure (HF) or acute HF. Most often, MCS has emerged as a bridge to transplantation, but more recently it is also used as a destination therapy. Mechanical circulatory support includes left ventricular assist device (LVAD) or bi-ventricular assist device (Bi-VAD). Currently, 2- to 3-year survival in carefully selected patients is much better than with medical therapy. However, MCS therapy is hampered by sometimes life-threatening complications including bleeding and device thrombosis. Von Willebrand factor (vWF) has two major functions in haemostasis. First, it plays a crucial role in platelet-subendothelium adhesion and platelet-platelet interactions (aggregation). Second, it is the carrier of factor VIII (FVIII) in plasma. Von Willebrand factor prolongs FVIII half-time by protecting it from proteolytic degradation. It delivers FVIII to the site of vascular injury thus enhancing haemostatic process. On one hand, high plasma levels of vWF have been associated with an increased risk of thrombosis. On the other, defects or deficiencies of vWF underlie the inherited von Willebrand disease or acquired von Willebrand syndrome. Here we review the pathophysiology of thrombosis and bleeding associated with vWF.

Fluctuations of Exercise Capacity in Patients After Kidney Transplantation

INTRODUCTION The aim of this study was to assess changes in the exercise capacity in subjects with end-stage renal failure undergoing kidney transplantation. MATERIALS AND METHODS The study group consisted of 16 subjects (9 males and 7 females) of mean age 43.3 +/- 11 years. The control group was composed of 7 healthy subjects (4 males and 3 females) of mean age 43.9 +/- 10 years. The first visit took place at 4-8 weeks after transplantation. Consecutive visits were scheduled for months 4, 10, 16, 24, 36, and 48 thereafter. Heart function was assessed using echocardiography and, an exercise test with analysis of peak oxygen consumption (VO(2)max). Results were correlated with VO(2)max (Pearson). The Mann-Whitney U test was used to compare study and control groups. RESULTS The results of eligible VO(2)max tests were as follows (medians and ranges): 1 month (n = 15), 19.5 (8.8-27.5) mL/kg/min; 4 months (n = 9), 21.7 (16.0-29.3) mL/kg/min; 10 months (n = 8), 23.3 (13.1-30.0) mL/kg/min; 16 months (n = 9), 26.6 (18.3- 36.0) mL/kg/min; 24 months (n = 9), 22.3 (14.1-35.0) mL/kg/min; 36 months (n = 9) 20.9 (16.4-32.1) mL/kg/min; 48 months (n = 5), 19.7 (17.0-30.9) mL/kg/min; versus 26.8 (26.5-42.5) mL/kg/min in the control group. VO(2)max results achieved by the study group were significantly lower than that in the control group, except for months 16, 24, and 48. VO(2)max was significantly negatively correlated with the following ultrasound parameters: interventricular septum diastolic and systolic diameter, and left ventricle systolic volume. CONCLUSION The exercise capacity of recipients seemed to be negatively affected by poor blood pressure control, resulting in heart muscle hypertrophy.