Accelerated atherosclerosis, hyperlipoproteinemia and insulin resistance in long-term survivors of Hodgkin lymphoma during childhood and adolescence.

Long-term survivors of Hodgkin lymphoma during childhood or adolescence (HL survivors) are at high risk of developing treatment-related late cardiovascular sequelae. In our study we evaluated the presence of modifiable cardiovascular risk factors (hypertension, hyperlipoproteinemia, hyperinsulinemia, obesity), endothelial and inflammatory markers (E-selectin, PAI-1, hs-CRP) and atherosclerotic changes in the common carotid arteries. Assessment was performed in 80 young adult Hodgkin lymphoma long-term survivors at more than 10 years after the potentially cardiovascular toxic anticancer treatment (median age at evaluation 34.7 years; range 24.1-40.9 years). The HL survivors were compared with 83 age- and gender-matched healthy volunteers. The HL survivors showed unfavorable lipid profiles compared to those of healthy controls: triglycerides (p=0.01), total cholesterol (p=0.0004), low density lipoprotein cholesterol (p=0.005). In HL survivors, we found a higher prevalence of hypertension (p=0.004) and insulin resistance - HOMA-IR (p=0.0002). Ultrasonographic examination of both common carotid arteries revealed a higher prevalence of atherosclerotic plaques (p=0.0009) and higher carotid intima-media thickness (p<0.0001) in HL survivors. Markers of oxidative stress (advanced oxidation protein products, oxidized low-density lipoprotein), inflammation (hs-CRP) and endothelial dysfunction (E-selectin, PAI-1) were also higher in HL survivors (p<0.0001, p=0.0002, p=0.0031, p=0.0087, p=0.004, respectively). Adult survivors of Hodgkin lymphoma during childhood and adolescence need closer follow-up with screening of metabolic syndrome components, unfavorable lifestyle factors and early management of these risk factors.

[Clinical biochemistry methods in objectiva evalution of overeating foood of carnivores (meat)by a phylogenetically herbivorous homo sapiens (a patient).]

The abuse of food of carnivores (meat) by phylogeneticallyI herbivorous Homo sapiens (a patient) initiates atherosclerosis. Addressing biogenetic law of E. Haeckel that ontogeny recapitulates phylogeny (a universal anamnesis), we suggest a diagnostic technique that allows evaluation of the meat diet abuse by a herbivorous Homo sapiens. This technique is based on application of phylogenetic theory of general pathology to clinical practice. The degrees of objective evaluation of nonphysiological overeating of meat are: the first, an increase in the fast plasma content of oleic triglycerides palmitoyl-oleyl-palmitate (POP). The second, hyperglyceridemia + an increase in low density lipoprotein cholesterol (LDL-CL) content. The third, increased plasma content of apoС-III. The fourth, an increase in the concentration of apoВ-48. If electrophoregrams are analyzed and hyperlipoproteinemia (HLP) type is determined according to WHO classification, the first degree of meat overeating is not informative, the second, corresponds to type IV HLP; the third, to type IIb HLP, and the forth, to type V HLP, i.e, the patient diet consists practically of the food of carnivores. Hyperlipoproteinemia coincides with insulin resistance syndrome, hyperglycemia and hyperinsulinemia, which is based on blood increase of fatty acids in the form of polar unesterified fatty acids (UFA). According to phylogenetic theory of general pathology, in vivo cells do not internalize glucose if there is a possibility to internalize UFA. Preventive examination allows evaluation of disorders in the biological function of trophology (food consumption). Thus, the use of different methods in the analysis of this function offers evaluation of the effectiveness of diet therapy from the level of disorders when treatment was started.

Aortic valve calcium score in hypercholesterolemic patients with and without low-density lipoprotein receptor gene mutation.

The aim of this study was a comparison of aortic valve calcium score (AVCS) between patients with hypercholesterolemia and genetic diagnosis of familial hypercholesterolemia with low-density lipoprotein receptor gene mutation (LDLR-M group), versus patients with hypercholesterolemia without LDLR gene mutation (LDLR-WT group). A total of 72 LDLR-M patients and 50 LDLR-WT patients were enrolled in the study and underwent CT as a part of an assessment of coronary calcium scoring. AVCS was determined and compared between the two patient groups. AVCS was significantly higher in the LDLR-M group in comparison to the LDLR-WT group (13.8 ± 37.9 vs. 0.94 ± 3.1, p = 0.03). The Yates' chi-squared test for independence revealed that LDLR mutation and AVCS were significantly dependable (Chi^2 = 6.106, p = 0.013). The LDLR mutation was a strong predictor of a high AVCS (OR 7.83, 95% CI 2.08-29.50, p = 0.002) on multivariate regression analysis. Among the traditional risk factors, age (odds ratio 1.12, 95% CI 1.05-1.18, p<0.001) and SBP (OR 1.04, 95% CI 1.00-1.07, p = 0.045) were also significant for high result of AVCS. An assessment of computed tomography calcium scores showed that LDLR-M patients have increased AVCS in comparison to those with LDLR-WT. In addition, LDLR mutation can be considered as an independent risk factor of having high AVSC even after adjustment for risk factors including cholesterol levels. This may result from the associated process connected with the regulatory role of LDLR in evolution of aortic valve calcifications.

[Clinical biochemistry methods in objectiva evalution of overeating foood of carnivores (meat) by a phylogenetically herbivorous homo sapiens (a patient).]

The abuse of food of carnivores (meat) by phylogeneticallyI herbivorous Homo sapiens (a patient) initiates atherosclerosis. Addressing biogenetic law of E. Haeckel that ontogeny recapitulates phylogeny (a universal anamnesis), we suggest a diagnostic technique that allows evaluation of the meat diet abuse by a herbivorous Homo sapiens. This technique is based on application of phylogenetic theory of general pathology to clinical practice. The degrees of objective evaluation of nonphysiological overeating of meat are: the first, an increase in the fast plasma content of oleic triglycerides palmitoyl-oleyl-palmitate (POP). The second, hyperglyceridemia + an increase in low density lipoprotein cholesterol (LDL-CL) content. The third, increased plasma content of apoС-III. The fourth, an increase in the concentration of apoВ-48. If electrophoregrams are analyzed and hyperlipoproteinemia (HLP) type is determined according to WHO classification, the first degree of meat overeating is not informative, the second, corresponds to type IV HLP; the third, to type IIb HLP, and the forth, to type V HLP, i.e, the patient diet consists practically of the food of carnivores. Hyperlipoproteinemia coincides with insulin resistance yndrome, hyperglycemia and hyperinsulinemia, which is based on blood increase of fatty acids in the form of polar unesterified fatty acids (UFA). According to phylogenetic theory of general pathology, in vivo cells do not internalize glucose if there is a possibility to internalize UFA. Preventive examination allows evaluation of disorders in the biological function of trophology (food consumption). Thus, the use of different methods in the analysis of this function offers evaluation of the effectiveness of diet therapy from the level of disorders when treatment was started.

Lipoprotein apheresis in patients with peripheral artery disease and lipoprotein(a)-hyperlipoproteinemia: 2-year follow-up of a prospective single center study.

OBJECTIVE: Elevated plasma levels of lipoprotein(a) [Lp(a)], referred to as lipoprotein(a)-hyperlipoproteinemia [Lp(a)-HLP], are an independent risk factor for atherosclerosis. Lipoprotein apheresis (LA) enables an effective reduction of Lp(a) plasma levels. The present study investigates the effects of LA in patients with Lp(a)-HLP and peripheral artery disease (PAD). METHODS: Ten patients with isolated Lp(a)-HLP and severe PAD and who had recently undergone a revascularization (index procedure) were prospectively included in this observational single center study. All patients received weekly LA. Ankle-brachial-index (ABI), transcutaneous partial oxygen pressure (tcpO2), pain level, and walking distance were assessed at baseline and at the follow ups scheduled 1, 3, 6, 12, and 24 months after initiation of LA. The number of revascularizations within 12 months prior and within 24 months after the index procedure was determined. RESULTS: As early as 1 month after initiation of LA, all investigated parameters had improved significantly compared to baseline. This improvement was further substantiated under LA throughout the entire follow-up period. Comparing baseline results with the 24-month follow-up, the average ABI increased from 0.53 ± 0.15 to 0.97 ± 0.08 (P < 0.001). The mean tcpO2 also increased from 42.9 ± 2.3 mmHg to 61 ± 4.6 mmHg (P < 0.001). The improved perfusion led to a reduction of the mean pain level from 7.0 ± 1.5 to 1.1 ± 0.4 (P < 0.001) on a visual analogue scale (VAS) and an extension of the mean walking distance from 87 ± 60 m to 402 ± 119 m (P < 0.001). All patients suffered from severe PAD with a high number of revascularizations in the 12 months prior to the index procedure (35 procedures in 120 patient-months). Since initiation of LA, the number of revascularizations dropped significantly and remained very low during the entire follow-up period (2 procedures in 229 patient-months, P < 0.001). CONCLUSION: In patients with Lp(a)-HLP and severe PAD, LA results in sustained improvement of circulation, pain level and walking distance. The number of repeat revascularizations is strongly reduced under LA treatment.

Alteraciones en la distensibilidad arterial de pacientes dislipidémicos / Alterations in arterial compliance of dyslipidemic patients

Introducción: Se estudió la alteración en la distensibilidad de las paredes arteriales producidas por la dislipidemia dependiente de c-LDL a lo largo de las distintas décadas de la vida, utilizando el análisis de onda de pulso radial. Métodos: Se efectuó el registro de onda de pulso en la arteria radial mediante un transductor de movimiento apoyado sobre la zona de palpación, sobre un conjunto de 100 varones dislipidémicos sin otros factores de riesgo, de edades comprendidas entre la 3.a y la 6.a décadas de la vida. Se calculó en cada caso el índice de aumentación. También se identificó en los registros la onda reflejada y se definió un coeficiente de velocidad como el cociente entre la talla del individuo y el tiempo transcurrido entre el máximo de la onda sistólica y el instante de llegada de dicha onda. Los resultados se compararon con los de un conjunto de 161 voluntarios sanos. Resultados: Se halló que los dislipidémicos presentaron valores del índice de aumentación similares a los controles hasta la 4.a década, aumentando a partir de entonces, con diferencias significativas a partir de la 6.a década. No se hallaron diferencias significativas en el índice de velocidad en ninguna de las edades estudiadas. Conclusiones: Se concluye que las alteraciones producidas por la dislipidemia requieren décadas para manifestarse, y comienzan afectando al mecanismo de vasodilatación de las arterias distales con mayor proporción de músculo liso, sin alterar las arterias de conducción proximales con mayor contenido de elastina

Introduction: We studied the alteration on the distensibility of the arterial walls caused by dyslipidemia LDLc dependent, along the decades of life, by means of a study of the radial artery pulse wave. Methods: We made an analysis of the radial artery pulse wave records acquired by means a movement displacement sensor, placed on radial palpation area. We recruited 100 dyslipidemic men without other cardiovascular risk factors, between the 3rd and the 6th decade. We identified the reflected wave in the records and we computed the augmentation index in order to quantify its amplitude and position. This index is useful to assess the endothelial dysfunction. Besides, we defined a velocity coefficient as the ratio between the size of the individuals and the delay time between the peak of the systolic wave and the arrival of the reflected wave. Results were compared against those obtained in a group of 161 healthy volunteers. Results: We found that dyslipidemic patients presented augmentation index values similar to controls until the fourth decade, increasing thereafter with significant differences only in the 6th decade. No significant differences were found in the velocity index in any of the ages studied. Conclusions: We conclude that alterations produced by dyslipidemia take decades to manifest, and they begin affecting the mechanism of vasodilation of distal arteries with highest proportion of smooth muscle, without altering the proximal conduit arteries with more elastin content

Postprandial lipemia as a cardiometabolic risk factor.

High levels of fasting circulating triglycerides (TG) represent an independent risk factor for cardiovascular disease. In western countries, however, people spend most time in postprandial conditions, with continuous fluctuation of lipemia due to increased levels of TG-rich lipoproteins (TRLs), including chylomicrons (CM), very low density lipoproteins (VLDL), and their remnants. Several factors contribute to postprandial lipid metabolism, including dietary, physiological, pathological and genetic factors. The presence of coronary heart disease, type 2 diabetes, insulin resistance and obesity is associated with higher postprandial TG levels compared with healthy conditions; this association is present also in subjects with normal fasting TG levels. Increasing evidence indicates that impaired metabolism of postprandial lipoproteins contributes to the pathogenesis of coronary artery disease, suggesting that lifestyle modifications as well as pharmacological approaches aimed at reducing postprandial TG levels might help to decrease the cardiovascular risk.

Effect of heparin-induced extracorporeal lipoprotein apheresis on renal function.

During the course of heparin-induced extracorporeal lipoprotein apheresis, a patient with no prior known renal impairment or proteinuria demonstrated sustained improvement in estimated glomerular filtration rate, commensurate with reduction in serum lipids and creatine phosphokinase levels. Causes and implications of this observation, which was not a priori, are discussed.

[Treating the symptoms in nephrotic syndrome: which therapeutic strategies are evidence based in the treatment of proteinuria?]. / Symptomatische Therapie bei nephrotischem Syndrom: Was ist gesichert in der Therapie der Proteinurie?.

Glomerular diseases are among the most common renal pathologies leading frequently to end-stage renal disease. Clinical disease can be divided into five different groups the features of which are determined by the underlying pathophysiology. One of these five clinical syndromes is the nephrotic syndrome, which is characterized by proteinuria > 3.5 g/day accompanied by hypalbuminemia, hyperlipoproteinemia and pronounced edema. The nephrotic syndrome may be the clinical manifestation of a row of underlying diseases. The pathophysiological basics had remained elusive for decades, yet recently significant progress which allows for establishing new therapeutic strategies has been made. A major breakthrough in understanding the function of the glomerular filter unit has been possible in the last years through both genetic and cell biological studies, which have revealed a crucial role for the visceral epithelial cells of the glomerulus - the podocytes. By now various factors have been found causing podocyte damage, such as toxines, immunological phenomena or systemic disease like diabetes mellitus.

Pokkuri Death Syndrome; sudden cardiac death cases without coronary atherosclerosis in South Asian young males.

Sudden death is one of the major concerns in forensic medicine. Especially when the deceased is a young subject without significant history, the case will be of major interest to the authorities. Sudden unexplained cardiac death has been known as "Pokkuri Death Syndrome" (PDS) in Japan, "Lai Tai" in Thailand, "Bangungut" in the Philippines, "Dream Disease" in Hawaii, and "Sudden Unexpected Nocturnal Death Syndrome" among South Asian immigrants in the USA. However, the clinical and pathological features of these sudden death cases, especially the characteristics of no coronary atherosclerosis, are surprisingly similar and mainly occur among Southeast Asian young males during sleep in the midnight. In this manuscript, we have reviewed the pathological characteristics and the possible mechanism of death in PDS cases, which were associated with significantly elevated remnant lipoproteins in plasma as revealed from our studies during the past 15 years in Japan. Although elevated plasma remnant lipoproteins have been known to be strongly atherogenic, coronary atherosclerosis was not observed in PDS cases. PDS cases were shown to be an interesting cardiovascular disease death discovered in forensic medicine research, which may suggest the difference between the occurrence of cardiovascular events and the severity of coronary atherosclerosis as separate factors. These observations in PDS cases suggest the possibility that the intervention could be more targeted to suppress the cardiovascular events rather than to slow down the progression of atherosclerosis, which is now most extensively targeted for the therapy of cardiovascular disease in Western countries.

[Correlation between acute coronary syndrome, hyperlipoproteinemia and statins].

Atherosclerosis is defined as a chronic, progressive, proliferative and inflammatory process developed as a response of blood vessel endothelium to the numerous noxious factors. The definition, which is only an approximate one, shows that one of the terms to carry definition is progression. In other words, it is a well-known fact today that atherosclerosis is a progressive process. The question about the possibilities of its stagnation and regression arises. The appearance of statins and their introduction into the therapy and the process of prevention give a positive answer to the previous question. The results of many studies have also shown that statins can be used to decrease and even stop the process of atherosclerosis. Using the modern diagnostic procedures, primarily the intravascular and Doppler ultrasound, andfocusing on regression, these studies fillowed the process of atherosclerosis in patients with statin therapy. The conclusions of these studies have indicated a clear degree of regression of atherosclerosis which is not a spectacular one, but implies the significant clinical improvement.

Insights into the effects of hyperlipoproteinemia on cyclosporine A biodistribution and relationship to renal function.

The purpose of this study was to assess the effect of hyperlipoproteinemia on the biodistribution of cyclosporine A (CyA), an extensively lipoprotein bound immunosuppressant, in a rat model and to determine the potential toxicological significance of this effect. Normolipidemic and hyperlipoproteinemic rats were given a single 5 mg/kg dose of CyA as intravenous bolus and at selected times postdose, tissues, blood, and plasma were harvested and assayed for CyA content. Hyperlipoproteinemia was induced by intraperitoneal injection of 1 g/kg poloxamer 407. Compared with normolipidemic animals, hyperlipoproteinemic rats had higher plasma, blood, kidney, and liver CyA concentrations. In contrast, in heart and spleen the concentrations were decreased in hyperlipoproteinemia. The nephrotoxic effect of CyA was also evaluated in normolipidemic and hyperlipoproteinemic rats after 7 days of dosing with 20 mg/kg/day. In both groups of animals, repeated doses of CyA were associated with equivalent decreases in creatinine and urea clearances compared with matching control and predose baseline measures. The concentrations of drug in kidney were equivalent at the conclusion of the study. However, despite these similarities there was microscopic evidence of more severe changes in the kidneys in the hyperlipoproteinemic rats, which also experienced a significant decrease in body weight compared with the normolipedemic animals. In conclusion, the distribution of CyA to kidneys was enhanced in poloxamer 407-induced hyperlipoproteinemic rats after single doses, and with repeated doses there was an apparent greater adverse effect on these animals compared with normolipidemic animals.

Effect of short term treatment with simvastatin and atorvastatin on lipids and paraoxonase activity in patients with hyperlipoproteinaemia.

OBJECTIVE: High-density lipoprotein (HDL)-associated paraoxonase (PON) activity may play an important role in the inhibition of low-density lipoprotein (LDL) oxidation. Previous studies have demonstrated that serum PON activity is decreased in patients with hyperlipoproteinaemia and coronary heart disease. The study presented here examined the effect of short-term treatment with simvastatin and atorvastatin on lipids and PON activity in patients with hyperlipoproteinaemia. RESEARCH DESIGN AND METHODS: A prospective, non-blinded, single-group, cross-over, comparative trial was performed. Following an 8-week dietary run-in period, 49 patients (23 men and 26 women, mean age: 59.8 +/- 7.9 years) with Fredrickson type IIa. and IIb. hyperlipoproteinaemias were randomized to receive either simvastatin 20 mg/day or atorvastatin 10 mg/day for 3 months. Following an 8-week washout period, patients were crossed-over to receive the other drug for a further 3 months. Serum lipids were measured and serum PON activity was determined spectrophotometrically using paraoxon as a substrate. RESULTS: Simvastatin treatment significantly reduced serum cholesterol, LDL-cholesterol (LDL-C) and apolipoprotein (apo) B levels (p < 0.001). Atorvastatin had a more pronounced cholesterol, LDL-C- and apo B-lowering effect (p < 0.001) compared with simvastatin. Both statins also significantly reduced serum triglyceride levels (p < 0.01). Simvastatin and atorvastatin caused no significant change in the levels of HDL-cholesterol (HDL-C) and apo A1. HDL-associated PON activity did not change significantly after simvastatin therapy, but significantly increased after atorvastatin treatment (p < 0.05). CONCLUSIONS: Short-term administration of simvastatin did not increase PON activity. Atorvastatin treatment had a favourable effect on lipid profile and increased the activity of HDL-associated PON.

Low-density lipoprotein particle number and risk for cardiovascular disease.

The key role played by low-density lipoprotein (LDL) particles in the pathogenesis of coronary heart disease (CHD) is well accepted, as is the benefit of lowering LDL in high-risk patients. What remains controversial is whether we are using the best measure(s) of LDL to identify all individuals who would benefit from therapy. Many studies have shown that, at a given level of LDL cholesterol, individuals with predominantly small LDL particles (pattern B) experience greater CHD risk than those with larger-size LDL. However, it is not clear from this observation that small LDL particles are inherently more atherogenic than large ones because, at a given level of LDL cholesterol, individuals with small LDL have more LDL particles in total. The phenotype of small LDL particle size co-segregates with a cluster of metabolic factors, including elevated triglycerides and reduced HDL cholesterol, and in multivariate analyses has generally been found not to be independently associated with CHD risk. In contrast, LDL particle number measured by nuclear magnetic resonance has consistently been shown to be a strong, independent predictor of CHD.

Pre-heparin lipoprotein lipase mass.

Lipoprotein lipase (LPL) is a lipolytic enzyme involved in catalyzing the hydrolysis of triglycerides (TG) in chylomicrons and very low-density lipoprotein (VLDL) particles. Over the last decade, the clinical significance of measuring LPL mass without heparin injection has been increasingly studied. In earlier studies, it was shown that this marker was utilized to classify type 1 hyperlipoproteinemia, which is an extremely rare metabolic disorder. Later, researchers paid more attention to the clinical significance of measuring this parameter in more common metabolic disorders. Studies have shown that pre-heparin plasma LPL mass has significant relationships with serum lipid and lipoproteins, visceral fat area, and even a marker for acute inflammation, although this might be a metabolic surrogate marker which does not appear to be involved in catalyzing the hydrolysis of TG in TG-rich lipoproteins. We suggest that pre-heparin LPL mass in plasma or sera provides us with useful and important information on the pathophysiology of metabolic disorders or acute inflammation despite its simplicity from a practical point of view.

[The influence of the experimental hyperlipoproteinemia on lipid composition and infrared spectrum of hypothalamic and hippocampal tissues]. / Vliianie éksperimental'noi giperlipoproteinemii na lipidnyi sostav i pokazateli infrakrasnogo spektra tkanei gipotalamusa i gippokampa.

Lipid composition and parameters of infrared (IR) spectrum of the tissues controlling heart activity (hypothalamus and hippocamp) were studied in rabbits with experimental hyperlipoproteinemia. Thin-layer chromatography discovered that in atherogenic dislipoproteinemia hypothalamic and hippocampal cholesterol, triglycerides, free fatty acids and phospholipids occurred in higher quantities while the levels of phosphatidylcholines and phosphatidylserines were subnormal. Altered parameters of IR-spectrum of hypothalamic and hippocampal tissue homogenates in atherogenesis were seen in the regions reflecting specific features of structural organization of water molecules. The analysis of the data allows the conclusion that disturbed structural transformation of water in the central nervous system in atherosclerosis is an important link of pathogenesis of electric heart unstability which may result in a sudden cardiac death.

[Metabolic syndrome and the pancreas. Status of blood circulation in the pancreas in metabolic syndrome in patients with different types of hyperlipoproteinemia ]. / Metabolicheskii sundrom i podzheludochnaia zheleza sostoianien krovoobrashcheniia v podzheludochnoi zheleze pri metabolicheskom sindrome u patsientov s razlichnym tipami giperipoproteinemii.

A study of blood circulation in the pancreas of 42 patients with the metabolic syndrome by the method of intracavitary rheography revealed a drop in the intensity of terminal blood circulation and presence of venous congestion with the activation of venous-arterial shunting. Hemodynamic disorders directly depended on the adiposity degree and patients' age, being evident as signs of a more obvious disorder of terminal blood circulation in patients with HLP of the II and III type.