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Endothelial function, antioxidant status and vascular compliance in newly diagnosed HFE C282Y homozygotes
Abstract
This pilot study was aimed to establish techniques for assessing and observing trends in endothelial function, antioxidant status and vascular compliance in newly diagnosed HFE haemochromatosis during the first year of venesection.
Untreated newly diagnosed HFE haemochromatosis patients were tested for baseline liver function, iron indices, lipid profile, markers of endothelial function, anti-oxidant status and vascular compliance. Following baseline assessment, subjects attended at 6-weeks and at 3, 6, 9 and 12-months for follow-up studies.
Ten patients were recruited (M=8, F=2, mean age=51 years). Venesection significantly increased high density lipoproteins at 12-months (1.25mmol/L vs. 1.37mmol/L, p=0.01). However, venesection did not significantly affect lipid hydroperoxides, intracellular and vascular cell adhesion molecules or high sensitivity C-reactive protein (0.57μmol/L vs. 0.51μmol/L, p=0.45, 427.4ng/ml vs. 307.22ng/ml, p=0.54, 517.70ng/ml vs. 377.50ng/ml, p=0.51 and 290.75μg/dL vs. 224.26μg/dL, p=0.25). There was also no significant effect of venesection on anti-oxidant status or pulse wave velocity (9.65m/s vs. 8.74m/s, p=0.34).
Venesection significantly reduced high density lipoproteins but was not associated with significant changes in endothelial function, anti-oxidant status or vascular compliance. Larger studies using this established methodology are required to clarify this relationship further.
... Vascular endothelial cells (VECs) are one of the target cells that are injured by iron overload [2,3]. Many clin-ical studies have shown that the patients of hereditary/hemolytic/hemorrhagic diseases or hemodialysis might suffer from VEC injury caused by either iron overload or iron accumulation [4][5][6][7][8][9][10][11][12][13]. An iron chelator was effective in clinical treatment [14]. ...
... Human umbilical vein endothelial cells (HUVECs) were purchased from the China Infrastructure of Cell Line Resources (Shanghai, China). Male C57BL/6J mice, [8][9][10] weeks old, weighing 20-22 g, were provided by the Animal Center of Nanchang University (Nanchang, China). ...
... HUVECs in the Eda group or CsA group were treated similar to those in the iron group, and in addition, cells were coincubated with 100 μM Eda or 1 μM CsA for 48 hours, respectively [39,40]. At 4,8,16,24,and 48 hours after the addition of iron-D, intracellular ROS generation and mitochondrial ROS generation of cells in each group were determined, respectively. At the end of experiments, the cell viability and LDH activity were determined. ...
It has been recognized that iron overload may harm the body’s health. Vascular endothelial cells (VECs) are one of the main targets of iron overload injury, and the mechanism involved was thought to be related to the excessive generation of reactive oxygen species (ROS). However, the subcellular and temporal characteristics of ROS generation, potential downstream mechanisms, and target organelles in VECs injured by iron overload have not been expounded yet. In this study, we elucidated the abovementioned issues through both in vivo and in vitro experiments. Mice were fed pellet diets that were supplemented with iron for 4 consecutive months. Results showed that the thoracic aortic strips’ endothelium-dependent dilation was significantly impaired and associated with inflammatory changes, noticeable under brown TUNEL-positive staining in microscopy analysis. In addition, the serum content of asymmetric dimethylarginine (ADMA) increased, whereas nitric oxide (NO) levels decreased. Furthermore, the dimethylarginine dimethylaminohydrolase II (DDAHII) expression and activity, as well as the phosphorylation of endothelial nitric oxide synthase (eNOS) in aortic tissue, were inhibited. Human umbilical vein endothelial cells were treated with 50 μ M iron dextran for 48 hours, after which the cell viability, NO content, DDAHII expression and activity, and phosphorylation of eNOS decreased and lactate dehydrogenase and caspase-3 activity, ADMA content, and apoptotic cells significantly increased. After the addition of L-arginine (L-Arg) or pAD/DDAHII, the abovementioned changes were reversed. By dynamically detecting the changes of ROS generation in the cytoplasm and mitochondria and interfering with different aspects of signaling pathways, we have confirmed for the first time that excessive ROS originates from the cytoplasm and activates the ROS-induced ROS release (RIRR) mechanism, leading to mitochondrial dysfunction. Together, our data suggested that excessive free iron ions produced excess ROS in the cytoplasm. Thus, excess ROS create one vicious circle by activating the ADMA/eNOS/DDAHII/NO pathway and another vicious circle by activation of the RIRR mechanism, which, when combined, induce a ROS burst, resulting in mitochondrial dysfunction and damaged VECs.
... Лікування таких травм завжди пов'язане з тривалою іммобілізацією всього організму. За даними окремих дослідників (Stogov, 2009;Narymbetova et al., 2011;Soubeyrand et al., 2013), унаслідок тривалої вимушеної нерухомості розвивається складний симптомокомплекс, ключовими ланками якого є пригнічення у тканинах СМ аеробного та активація анаеробного шляху утилізації глюкози, зниження енергозабезпечення, порушення транспорту різних іонів (Sazontova et al., 2007), зміна кислотно-лужного балансу (Ivanov, 2002;Ciobica et al., 2010) на фоні ішемії, яка виникає поступо (Machovic et al., 2013), дефіциту кисню (Mickan and Popel, 2001;Willis, 2011) та активації процесів перекисного окислення ліпідів (Kamskova, 2001;Cash et al., 2014). ...
... Результати досліджень вказують на те, що вільні радикали порушують цілісність мембран лізосом і підвищують їх проникність для нуклеаз. Останні виходять у цитоплазму та пошкоджують геном клітин, що узгоджується з уявленнями багатьох авторів (Wielgat and Braszko, 2012;Machovic et al., 2013;Cash et al., 2014). ДГК супроводжується також активізацією локусів хроматину, які визначають синтез антитіл на певний вид білків. ...
... Із часу описання єдиної нейроно-гліо-капілярної метаболічної системи (Zhabotinskij, 1965) зацікавленість до взаємовідношень її складових компонентів невпинно зростає. І все ж питання про їх структурну перебудову за умов ДГК висвітлене недостатньо, має суперечливий характер Nechipurenko et al., 2008;Cash et al., 2014). Повідомлення про нейроцит-гліо-капілярні взає-мовідношення у СМ при ДГК практично відсутні. ...
The purpose of this paper is to study the morphological changes of neurocytes in spinal cord of rats in hypokinesia and subsequent physical loading. Studies were performed on 55 laboratory rats of Wistar line. Materials of the research were the anterior horns of the gray matter of L5-S2 spinal segments. Preparations stained by Nissl and Viktorov were examined histologically. Hypokinesia was modeled following on the author’s technique. It was established that during prolonged hypokinesia in neurocytes of spinal cord of rats morphological changes in cell size and shape of the motor nuclei of all segments under study have been recorded. The number of hypochromic, hyperchromic destructively unchanged and hyperchromic destructively altered neurocytes increase; shadow cells appears, as well as cases of satellitosis and neuronophagia. Decrease in of albumen synthetical neurocyte function has been recorded. Physical loading of the average aerobic capacity leads to normalization of structural and functional state of neurocytes and enhances the reparative processes, as evidenced by a number of positive changes in morphometric parameters: increase in the number of normochromic neurocytes and decreasing the number of hyper- and hypochromic neurocytes with destructive signs, absence of pyknotic forms. Morphological parameters of neurocytes and their nuclei after physical loading of average aerobic capacity do not differ from those in the control group of intact animals. In neurocytes of this group of rats RNA concentration increases by 12.6% compared to animals after prolonged hypokinesia. Neurocytes of spinal cord of rats after prolonged hypokinesia develop significant morphological changes which are characterized by emergence of a significant number of hyperchromic neurocytes with signs of destructive changes and shadow cells, as well as and hypochromic neurocytes with signs of destructive changes, reduction in size and change of shape of perikaryons of neurocytes and their nuclei. Morphological changes of neurocytes after prolonged hypokinesia are accompanied by violations of biosynthetic processes, as evidenced by RNA decrease in the cytoplasm of efferent neurocytes of spinal cord of rats. Physical loading of average aerobic capacity leads to normalization of structural and functional state of neurocytes and promotes the reparative processes suported by positive changes in morphometric parameters.
... Hypertriglyceridemia was found in almost a third of subjects with HH which was significantly decreased by phlebotomies [19] whereas in non-HH subjects with hyperferritinemia and hypertriglyceridemia repeated phlebotomies did not reduce triglyceride concentrations [20]. Reduced levels of LDL at baseline [10] and an increase of HDL under phlebotomy in HH patients were shown [21], but in their study no effect of phlebotomy was seen on total cholesterol, low density lipoprotein (LDL) and triglyceride levels [21]. Hence, iron has effects on hepatocellular metabolism of phospholipids and lipoproteins, and on unsaturation of fatty acids in experimental and clinical settings. ...
... Hypertriglyceridemia was found in almost a third of subjects with HH which was significantly decreased by phlebotomies [19] whereas in non-HH subjects with hyperferritinemia and hypertriglyceridemia repeated phlebotomies did not reduce triglyceride concentrations [20]. Reduced levels of LDL at baseline [10] and an increase of HDL under phlebotomy in HH patients were shown [21], but in their study no effect of phlebotomy was seen on total cholesterol, low density lipoprotein (LDL) and triglyceride levels [21]. Hence, iron has effects on hepatocellular metabolism of phospholipids and lipoproteins, and on unsaturation of fatty acids in experimental and clinical settings. ...
Background:
Hereditary hemochromatosis (HH) is an autosomal recessive genetic disorder with increased intestinal iron absorption and therefore iron Overload. iron overload leads to increased levels of toxic non-transferrin bound iron which results in oxidative stress and lipid peroxidation. The impact of iron on lipid metabolism is so far not fully understood. The aim of this study was to investigate lipid metabolism including lipoproteins (HDL, LDL), neutral (triglycerides, cholesterol) and polar lipids (sphingo- and phospholipids), and PNPLA3 polymorphism (rs738409/I148M) in HH.
Methods:
We conducted a cohort study of 54 subjects with HH and 20 healthy subjects. Patients were analyzed for their iron status including iron, ferritin, transferrin and transferrin saturation and serum lipid profile on a routine follow-up examination.
Results:
HH group showed significantly lower serum phosphatidylcholine (PC) and significantly higher phosphatidylethanolamine (PE) compared to healthy control group. The ratio of PC/PE was clearly lower in HH group indicating a shift from PC to PE. Triglycerides were significantly higher in HH group. No differences were seen for HDL, LDL and cholesterol. Hepatic steatosis was significantly more frequent in HH. PNPLA3 polymorphism (CC vs. CG/GG) did not reveal any significant correlation with iron and lipid parameters including neutral and polar lipids, grade of steatosis and fibrosis.
Conclusion:
Our study strengthens the hypothesis of altered lipid metabolism in HH and susceptibility to nonalcoholic fatty liver disease. Disturbed phospholipid metabolism may represent an important factor in pathogenesis of hepatic steatosis in HH.
... Hereditaer haemochromatosisban a lipidperoxidáció markereinek tekinthető tiobarbitursav-reaktív termékek (thiobarbituric acid reactive substances [TBARS]) emelkedett, ugyanakkor az alfa-tokoferol, aszkorbát, retinol csökkent szintjét írták le; kis esetszámú vizsgálatban a lipid-hidroperoxidok szintje nem emelkedett. A venasectio sem befolyásolta érdemben az antioxidáns-statust [37][38][39]. ...
Absztrakt
Az idült májbetegségek a megbetegedési és halálozási statisztikák vezető okai. A vírusfertőzések, toxikus bántalmak, anyagcsere-, autoimmun, tárolási betegségek okozta májkárosodások, a károsító hatás tartós fennállása esetén, a máj kötőszövetes átépüléséhez vezethetnek. A folyamat komplex, nem is minden részletében ismert; egyértelmű szerepük van benne sejteknek, citokinek, kemokinek felszabadulásának, bizonyos hepatokinek megváltozott elválasztásának, a lipotoxicitásnak, a veleszületett immunitásnak, a bélmikrobiomnak, a fémionoknak, valamint a szabad gyökös folyamatoknak is. Az idült májbetegségek gyakran tünetszegényen zajlanak, gyakran már csak a kötőszövetes átépülés, a májelégtelenség vagy a hepatocellularis carcinoma stádiumában kerülnek kórismézésre, amikor a kórjóslat rossz, és a kezelési lehetőségek is korlátozottak. A kutatások középpontját képezi olyan nem invazív, megfelelően érzékeny és fajlagos biomarkerek megtalálása, amelyek a májbiopszia szükségét csökkentik, a májban zajló folyamatot, a progresszióját jelezhetik, valamint a kezelés hatását is lemérik. A szerzők ismertetik a leggyakoribb idült májbetegségek progressziójában szerepet játszó folyamatokat, külön kitérve az egyes kórképekben a pro/antioxidáns egyensúlyt jellemző paraméterekre, hangsúlyozva egy kombinált biomarker szükségességét. Orv Hetil. 2020; 161(35): 1441–1448.
Iron overload causes vascular endothelium damage. It has been thought to relate excessive reactive oxygen species (ROS) generation. Tetramethylpyrazine (TMP), an active ingredient of Ligusticum chuanxiong Hort, protects various cells by inhibiting oxidative stress and cascade reaction of apoptosis. However, whether TMP can increase DDAHIIactivity and expression against endothelial cell damage induced by iron overload, and the protective mechanism has not been elucidated. In this study, 50 μM iron dextran and 25 μM TMP were used to co-treat HUVECs for 48 h. TMP could increase cell viability and decrease LDH activity, enhance DDAHIIexpression and activity, p-eNOS/eNOS ratio, NO content, and reduce ADMA level. TMP also showed a strong antioxidant activity with inhibited ROS generation and oxidative stress. Moreover, TMP attenuated mitochondrial membrane potential loss, inhibited mitochondrial permeability transition pore openness, and decreased apoptosis induced by iron overload. While mentioned above, the protective effects of TMP were abolished with the addition of pAD/DDAHII-shRNA. The effects of TMP against iron overload were similar to the positive control groups, L-arginine, a competitive substrate of ADMA, or edaravone, free radical scavenger. These results signify that TMP alleviated iron overload damage in vascular endothelium via ROS/ADMA/ DDAHII/eNOS/NO pathway.
BACKGROUND: In observational analyses, higher levels of high-density lipoprotein (HDL) cholesterol have been associated with a lower risk of coronary heart disease events. However, whether raising HDL cholesterol levels therapeutically reduces cardiovascular risk remains uncertain. Inhibition of cholesteryl ester transfer protein (CETP) raises HDL cholesterol levels and might therefore improve cardiovascular outcomes.
METHODS: We randomly assigned 15,871 patients who had had a recent acute coronary syndrome to receive the CETP inhibitor dalcetrapib, at a dose of 600 mg daily, or placebo, in addition to the best available evidence-based care. The primary efficacy end point was a composite of death from coronary heart disease, nonfatal myocardial infarction, ischemic stroke, unstable angina, or cardiac arrest with resuscitation.
RESULTS: At the time of randomization, the mean HDL cholesterol level was 42 mg per deciliter (1.1 mmol per liter), and the mean low-density lipoprotein (LDL) cholesterol level was 76 mg per deciliter (2.0 mmol per liter). Over the course of the trial, HDL cholesterol levels increased from baseline by 4 to 11% in the placebo group and by 31 to 40% in the dalcetrapib group. Dalcetrapib had a minimal effect on LDL cholesterol levels. Patients were followed for a median of 31 months. At a prespecified interim analysis that included 1135 primary end-point events (71% of the projected total number), the independent data and safety monitoring board recommended termination of the trial for futility. As compared with placebo, dalcetrapib did not alter the risk of the primary end point (cumulative event rate, 8.0% and 8.3%, respectively; hazard ratio with dalcetrapib, 1.04; 95% confidence interval, 0.93 to 1.16; P=0.52) and did not have a significant effect on any component of the primary end point or total mortality. The median C-reactive protein level was 0.2 mg per liter higher and the mean systolic blood pressure was 0.6 mm Hg higher with dalcetrapib as compared with placebo (P<0.001 for both comparisons).
CONCLUSIONS: In patients who had had a recent acute coronary syndrome, dalcetrapib increased HDL cholesterol levels but did not reduce the risk of recurrent cardiovascular events. (Funded by F. Hoffmann-La Roche; dal-OUTCOMES ClinicalTrials.gov number, NCT00658515.).
Background:
Increased levels of the inflammatory biomarker high-sensitivity C-reactive protein predict cardiovascular events. Since statins lower levels of high-sensitivity C-reactive protein as well as cholesterol, we hypothesized that people with elevated high-sensitivity C-reactive protein levels but without hyperlipidemia might benefit from statin treatment.
Methods:
We randomly assigned 17,802 apparently healthy men and women with low-density lipoprotein (LDL) cholesterol levels of less than 130 mg per deciliter (3.4 mmol per liter) and high-sensitivity C-reactive protein levels of 2.0 mg per liter or higher to rosuvastatin, 20 mg daily, or placebo and followed them for the occurrence of the combined primary end point of myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes.
Results:
The trial was stopped after a median follow-up of 1.9 years (maximum, 5.0). Rosuvastatin reduced LDL cholesterol levels by 50% and high-sensitivity C-reactive protein levels by 37%. The rates of the primary end point were 0.77 and 1.36 per 100 person-years of follow-up in the rosuvastatin and placebo groups, respectively (hazard ratio for rosuvastatin, 0.56; 95% confidence interval [CI], 0.46 to 0.69; P<0.00001), with corresponding rates of 0.17 and 0.37 for myocardial infarction (hazard ratio, 0.46; 95% CI, 0.30 to 0.70; P=0.0002), 0.18 and 0.34 for stroke (hazard ratio, 0.52; 95% CI, 0.34 to 0.79; P=0.002), 0.41 and 0.77 for revascularization or unstable angina (hazard ratio, 0.53; 95% CI, 0.40 to 0.70; P<0.00001), 0.45 and 0.85 for the combined end point of myocardial infarction, stroke, or death from cardiovascular causes (hazard ratio, 0.53; 95% CI, 0.40 to 0.69; P<0.00001), and 1.00 and 1.25 for death from any cause (hazard ratio, 0.80; 95% CI, 0.67 to 0.97; P=0.02). Consistent effects were observed in all subgroups evaluated. The rosuvastatin group did not have a significant increase in myopathy or cancer but did have a higher incidence of physician-reported diabetes.
Conclusions:
In this trial of apparently healthy persons without hyperlipidemia but with elevated high-sensitivity C-reactive protein levels, rosuvastatin significantly reduced the incidence of major cardiovascular events. (ClinicalTrials.gov number, NCT00239681.)
The dysmetabolic iron overload syndrome (DIOS) is now a frequent finding in the general population, as is detected in about one third of patients with nonalcoholic fatty liver disease (NAFLD) and the metabolic syndrome. The pathogenesis is related to altered regulation of iron transport associated with steatosis, insulin resistance, and subclinical inflammation, often in the presence of predisposing genetic factors. Evidence is accumulating that excessive body iron plays a causal role in insulin resistance through still undefined mechanisms that probably involve a reduced ability to burn carbohydrates and altered function of adipose tissue. Furthermore, DIOS may facilitate the evolution to type 2 diabetes by altering beta-cell function, the progression of cardiovascular disease by contributing to the recruitment and activation of macrophages within arterial lesions, and the natural history of liver disease by inducing oxidative stress in hepatocytes, activation of hepatic stellate cells, and malignant transformation by promotion of cell growth and DNA damage. Based on these premises, the association among DIOS, metabolic syndrome, and NAFLD is being investigated as a new risk factor to predict the development of overt cardiovascular and hepatic diseases, and possibly hepatocellular carcinoma, but most importantly, represents also a treatable condition. Indeed, iron depletion, most frequently achieved by phlebotomy, has been shown to decrease metabolic alterations and liver enzymes in controlled studies in NAFLD. Additional studies are warranted to evaluate the potential of iron reductive therapy on hard clinical outcomes in patients with DIOS.
Disturbances of iron homeostasis are associated with altered susceptibility to infectious disease, but the underlying molecular mechanisms are poorly understood. To study this phenomenon, we examined innate immunity to oral Salmonella infection in Hfe knockout (Hfe(-/-)) mice, a model of the human inherited disorder of iron metabolism type I hemochromatosis. Salmonella- and LPS-induced inflammatory responses were attenuated in the mutant animals, with less severe enterocolitis observed in vivo and reduced macrophage TNF-alpha and IL-6 secretion measured in vitro. The macrophage iron exporter ferroportin (FPN) was up-regulated in the Hfe(-/-) mice, and correspondingly, intramacrophage iron levels were lowered. Consistent with the functional importance of these changes, the abnormal cytokine production of the mutant macrophages could be reproduced in wild-type cells by iron chelation, and in a macrophage cell line by overexpression of FPN. The results of analyzing specific steps in the biosynthesis of TNF-alpha and IL-6, including intracellular concentrations, posttranslational stability and transcript levels, were consistent with reduced translation of cytokine mRNAs in Hfe(-/-) macrophages. Polyribosome profile analysis confirmed that elevated macrophage FPN expression and low intracellular iron impaired the translation of specific inflammatory cytokine transcripts. Our results provide molecular insight into immune function in type I hemochromatosis and other disorders of iron homeostasis, and reveal a novel role for iron in the regulation of the inflammatory response.
To examine the prevalence of coronary artery disease (CAD) in autopsies of patients with iron-overload syndromes.
Retrospective autopsy study of CAD in cases of hemochromatosis and multiorgan hemosiderosis.
Registry of nearly 48,000 autopsies performed at The Johns Hopkins Hospital between 1889 and 1992.
One hundred twenty-three subjects were studied. In a 2:1 control-case ratio, 82 controls matched by age, race, and sex were compared with 41 cases with iron overload.
Severity of CAD.
Pathological description of the coronary arteries were recorded as advanced or severe in 12% of iron-overload cases (n = 41) (mean age, 57.6 +/- 13.2 years) compared with 38% of controls (n = 82) (mean age, 57.0 +/- 13.8 years) (P = .01). The prevalence of three-vessel disease assessed by postmortem coronary arteriography was 11.1% in iron-overload cases (n = 18) (mean age, 61.7 +/- 12.2 years) compared with 33.3% in controls (n = 36) (mean age, 61.1 +/- 12.5 years) (P = .04). The odds ratio of CAD with iron overload was 0.18 (95% confidence interval, 0.04 to 0.73).
Iron overload resulting from hemochromatosis or multiorgan hemosiderosis is not associated with an increased prevalence of CAD.
Although it is generally accepted that lowering elevated serum levels of low-density lipoprotein (LDL) cholesterol in patients with coronary heart disease is beneficial, there are few data to guide decisions about therapy for patients whose primary lipid abnormality is a low level of high-density lipoprotein (HDL) cholesterol.
We conducted a double-blind trial comparing gemfibrozil (1200 mg per day) with placebo in 2531 men with coronary heart disease, an HDL cholesterol level of 40 mg per deciliter (1.0 mmol per liter) or less, and an LDL cholesterol level of 140 mg per deciliter (3.6 mmol per liter) or less. The primary study outcome was nonfatal myocardial infarction or death from coronary causes.
The median follow-up was 5.1 years. At one year, the mean HDL cholesterol level was 6 percent higher, the mean triglyceride level was 31 percent lower, and the mean total cholesterol level was 4 percent lower in the gemfibrozil group than in the placebo group. LDL cholesterol levels did not differ significantly between the groups. A primary event occurred in 275 of the 1267 patients assigned to placebo (21.7 percent) and in 219 of the 1264 patients assigned to gemfibrozil (17.3 percent). The overall reduction in the risk of an event was 4.4 percentage points, and the reduction in relative risk was 22 percent (95 percent confidence interval, 7 to 35 percent; P=0.006). We observed a 24 percent reduction in the combined outcome of death from coronary heart disease, nonfatal myocardial infarction, and stroke (P< 0.001). There were no significant differences in the rates of coronary revascularization, hospitalization for unstable angina, death from any cause, and cancer.
Gemfibrozil therapy resulted in a significant reduction in the risk of major cardiovascular events in patients with coronary disease whose primary lipid abnormality was a low HDL cholesterol level. The findings suggest that the rate of coronary events is reduced by raising HDL cholesterol levels and lowering levels of triglycerides without lowering LDL cholesterol levels.
Impaired endothelium-dependent, flow-mediated dilatation of the brachial artery was observed in a 50-year-old premenopausal female non-smoker with idiopathic hemochromatosis. Endothelial dysfunction observed in this patient supports a relationship between body iron stores and early atherosclerotic process.
Current methods for assessing vasomotor endothelial function are impractical for use in large studies. We tested the hypothesis that pulse-wave analysis (PWA) combined with provocative pharmacological testing might provide an alternative method. Radial artery waveforms were recorded and augmentation index (AIx) was calculated from derived aortic waveforms. Thirteen subjects received sublingual nitroglycerin (NTG), inhaled albuterol, or placebo. Twelve subjects received NTG, albuterol, and placebo separately during an infusion of N(G)-monomethyl-L-arginine (LNMMA) or norepinephrine. Twenty-seven hypercholesterolemic subjects and 27 controls received NTG followed by albuterol. Endothelial function was assessed by PWA and forearm blood flow in 27 subjects. Albuterol and NTG both significantly and repeatably reduced AIx (P<0.001). Only the response to albuterol was inhibited by LNMMA (-9.8+/-5.5% vs -4.7+/-2.7%; P=0.02). Baseline AIx was higher in the hypercholesterolemic subjects, who exhibited a reduced response to albuterol (P=0.02) but not to NTG when compared with matched controls. The responses to albuterol and acetylcholine were correlated (r=0.5, P=0.02). Consistent with an endothelium-dependent effect, the response to albuterol was substantially inhibited by LNMMA. Importantly, the response to albuterol was reduced in subjects with hypercholesterolemia and was correlated to that of intra-arterial acetylcholine. This methodology provides a simple, repeatable, noninvasive means of assessing endothelial function in vivo.
BACKGROUND:
Increased levels of the inflammatory biomarker high-sensitivity C-reactive protein predict cardiovascular events. Since statins lower levels of high-sensitivity C-reactive protein as well as cholesterol, we hypothesized that people with elevated high-sensitivity C-reactive protein levels but without hyperlipidemia might benefit from statin treatment.
METHODS:
We randomly assigned 17,802 apparently healthy men and women with low-density lipoprotein (LDL) cholesterol levels of less than 130 mg per deciliter (3.4 mmol per liter) and high-sensitivity C-reactive protein levels of 2.0 mg per liter or higher to rosuvastatin, 20 mg daily, or placebo and followed them for the occurrence of the combined primary end point of myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes.
RESULTS:
The trial was stopped after a median follow-up of 1.9 years (maximum, 5.0). Rosuvastatin reduced LDL cholesterol levels by 50% and high-sensitivity C-reactive protein levels by 37%. The rates of the primary end point were 0.77 and 1.36 per 100 person-years of follow-up in the rosuvastatin and placebo groups, respectively (hazard ratio for rosuvastatin, 0.56; 95% confidence interval [CI], 0.46 to 0.69; P<0.00001), with corresponding rates of 0.17 and 0.37 for myocardial infarction (hazard ratio, 0.46; 95% CI, 0.30 to 0.70; P=0.0002), 0.18 and 0.34 for stroke (hazard ratio, 0.52; 95% CI, 0.34 to 0.79; P=0.002), 0.41 and 0.77 for revascularization or unstable angina (hazard ratio, 0.53; 95% CI, 0.40 to 0.70; P<0.00001), 0.45 and 0.85 for the combined end point of myocardial infarction, stroke, or death from cardiovascular causes (hazard ratio, 0.53; 95% CI, 0.40 to 0.69; P<0.00001), and 1.00 and 1.25 for death from any cause (hazard ratio, 0.80; 95% CI, 0.67 to 0.97; P=0.02). Consistent effects were observed in all subgroups evaluated. The rosuvastatin group did not have a significant increase in myopathy or cancer but did have a higher incidence of physician-reported diabetes.
CONCLUSIONS:
In this trial of apparently healthy persons without hyperlipidemia but with elevated high-sensitivity C-reactive protein levels, rosuvastatin significantly reduced the incidence of major cardiovascular events. (ClinicalTrials.gov number, NCT00239681.)
2008 Massachusetts Medical Society
Pulse wave analysis in historical times. Interpretation of the arterial pulse has been an important part of the medical examination from ancient times. Graphic methods for clinical pulse wave recording were introduced by Marey in Paris and by Mahomed in London last century. Mahomed showed how such recordings could be used to detect asymptomatic hypertension, and used them to chart the natural history of essential hypertension and to distinguish between this condition and chronic nephritis. Interest in arterial pulse analysis, as applied by Mahomed, lapsed with the introduction of the cuff sphygmomanometer 100 years ago. Modern pulse wave analysis. Analysis of the arterial pulse is now regaining favour as limitations of the cuff sphygmomanometer are better recognized (including the ability only to measure extremes of the pulse in the brachial artery). In addition, high-fidelity tonometers have been introduced for very accurate, non-invasive measurement of arterial pulse contour, and there is now a better understanding of arterial hemodynamics, and appreciation of disease and aging effects in humans. It is now possible to record the pulse wave accurately in the radial or carotid artery, to synthesize the ascending aortic pulse waveform, to identify systolic and diastolic periods and to generate indices of ventricular-vascular interaction previously only possible with invasive arterial catheterization. Pressure pulse wave analysis now permits more accurate diagnosis and more logical therapy than was ever possible in the past.
Currentmethods for assessing vasomotor endothelial function are impractical for use in large studies. We tested the hypothesis that pulse-wave analysis (PWA) combined with provocative pharmacological testing might provide an alternative method. Radial artery waveforms were recorded and augmentation index (AIx) was calculated from derived aortic waveforms. Thirteen subjects received sublingual nitroglycerin (NTG), inhaled albuterol, or placebo. Twelve subjects received NTG, albuterol, and placebo separately during an infusion of N G-monomethyl-l-arginine (LNMMA) or norepinephrine. Twenty-seven hypercholesterolemic subjects and 27 controls received NTG followed by albuterol. Endothelial function was assessed by PWA and forearm blood flow in 27 subjects. Albuterol and NTG both significantly and repeatably reduced AIx ( P <0.001). Only the response to albuterol was inhibited by LNMMA (−9.8±5.5% vs −4.7±2.7%; P =0.02). Baseline AIx was higher in the hypercholesterolemic subjects, who exhibited a reduced response to albuterol ( P =0.02) but not to NTG when compared with matched controls. The responses to albuterol and acetylcholine were correlated ( r =0.5, P =0.02). Consistent with an endothelium-dependent effect, the response to albuterol was substantially inhibited by LNMMA. Importantly, the response to albuterol was reduced in subjects with hypercholesterolemia and was correlated to that of intra-arterial acetylcholine. This methodology provides a simple, repeatable, noninvasive means of assessing endothelial function in vivo.
Increased levels of the inflammatory biomarker high-sensitivity C-reactive protein predict cardiovascular events. Since statins lower levels of high-sensitivity C-reactive protein as well as cholesterol, we hypothesized that people with elevated high-sensitivity C-reactive protein levels but without hyperlipidemia might benefit from statin treatment. Methods We randomly assigned 17,802 apparently healthy men and women with low-density lipoprotein (LDL) cholesterol levels of less than 130 mg per deciliter (3.4 mmol per liter) and high-sensitivity C-reactive protein levels of 2.0 mg per liter or higher to rosuvastatin, 20 mg daily, or placebo and followed them for the occurrence of the combined primary end point of myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes. Results The trial was stopped after a median follow-up of 1.9 years (maximum, 5.0). Rosuvastatin reduced LDL cholesterol levels by 50% and high-sensitivity C-reactive protein levels by 37%. The rates of the primary end point were 0.77 and 1.36 per 100 person-years of follow-up in the rosuvastatin and placebo groups, respectively (hazard ratio for rosuvastatin, 0.56; 95% confidence interval [CI], 0.46 to 0.69; P<0.00001), with corresponding rates of 0.17 and 0.37 for myocardial infarction (hazard ratio, 0.46; 95% CI, 0.30 to 0.70; P = 0.0002), 0.18 and 0.34 for stroke (hazard ratio, 0.52; 95% CI, 0.34 to 0.79; P = 0.002), 0.41 and 0.77 for revascularization or unstable angina (hazard ratio, 0.53; 95% CI, 0.40 to 0.70; P<0.00001), 0.45 and 0.85 for the combined end point of myocardial infarction, stroke, or death from cardiovascular causes (hazard ratio, 0.53; 95% CI, 0.40 to 0.69; P<0.00001), and 1.00 and 1.25 for death from any cause (hazard ratio, 0.80; 95% CI, 0.67 to 0.97; P = 0.02). Consistent effects were observed in all subgroups evaluated. The rosuvastatin group did not have a significant increase in myopathy or cancer but did have a higher incidence of physician-reported diabetes. Conclusions
Objective.
—To examine the prevalence of coronary artery disease (CAD) in autopsies of patients with iron-overload syndromes.Design.
—Retrospective autopsy study of CAD in cases of hemochromatosis and multiorgan hemosiderosis.Setting.
—Registry of nearly 48000 autopsies performed at The Johns Hopkins Hospital between 1889 and 1992.Subjects.
—One hundred twenty-three subjects were studied. In a 2:1 control-case ratio, 82 controls matched by age, race, and sex were compared with 41 cases with iron overload.Main Outcome Measure.
—Severity of CAD.Results.
—Pathological description of the coronary arteries were recorded as advanced or severe in 12% of iron-overload cases(n=41) (mean age, 57.6±13.2 years) compared with 38% of controls (n=82) (mean age, 57.0±13.8 years) (P=.01). The prevalence of three-vessel disease assessed by postmortem coronary arteriography was 11.1% in iron-overload cases (n=18) (mean age, 61.7±12.2 years) compared with 33.3% in controls (n=36) (mean age, 61.1±12.5 years) (P=.04). The odds ratio of CAD with iron overload was 0.18 (95% confidence interval, 0.04 to 0.73).Conclusions.
—Iron overload resulting from hemochromatosis or multiorgan hemosiderosis is not associated with an increased prevalence of CAD.(JAMA. 1994;272:231-233)
Background: Both C-reactive protein and low-density lipoprotein (LDL) cholesterol levels are elevated in persons at risk for cardiovascular events. However, population-based data directly comparing these two biologic markers are not available. Methods: C-reactive protein and LDL cholesterol were measured at base line in 27,939 apparently healthy American women, who were then followed for a mean of eight years for the occurrence of myocardial infarction, ischemic stroke, coronary revascularization, or death from cardiovascular causes. We assessed the value of these two measurements in predicting the risk of cardiovascular events in the study population. Results: Although C-reactive protein and LDL cholesterol were minimally correlated (r=0.08), base-line levels of each had a strong linear relation with the incidence of cardiovascular events. After adjustment for age, smoking status, the presence or absence of diabetes mellitus, categorical levels of blood pressure, and use or nonuse of hormone-replacement therapy, the relative risks of first cardiovascular events according to increasing quartiles of C-reactive protein, as compared with the women in the lowest quintile, were 1.4, 1.6, 2.0, and 2.3 (P<0.001), whereas the corresponding relative risks in increasing quintiles of LDL cholesterol, as compared with the lowest, were 0.9, 1.1, 1.3, and 1.5 (P<0.001). Similar effects were observed in separate analyses of each component of the composite end point and among users and nonusers of hormone-replacement therapy. Overall, 77 percent of all events occurred among women with LDL cholesterol levels below 160 mg per deciliter (4.14 mmol per liter), and 46 percent occurred among those with LDL cholesterol levels below 130 mg per deciliter (3.36 mmol per liter). By contrast, because C-reactive protein and LDL cholesterol measurements tended to identify different high-risk groups, screening for both biologic markers provided better prognostic information than screening for either alone. Independent effects were also observed for C-reactive protein in analyses adjusted for all components of the Framingham risk score. Conclusions: These data suggest that the C-reactive protein level is a stronger predictor of cardiovascular events than the LDL cholesterol level and that it adds prognostic information to that conveyed by the Framingham risk score.
The purpose of this study was to evaluate independent associations of high-density lipoprotein cholesterol (HDL-C) and particle (HDL-P) concentrations with carotid intima-media thickness (cIMT) and incident coronary heart disease (CHD).
HDL-C is inversely related to CHD, and also to triglycerides, low-density lipoprotein particles (LDL-P), and related metabolic risk. HDL-P associations with CHD may be partially independent of these factors.
In a multiethnic study of 5,598 men and women ages 45 to 84 years old, without baseline CHD, excluding subjects on lipid-lowering medications, triglycerides >400 mg/dl, or missing values, we evaluated associations of HDL-C and nuclear magnetic resonance spectroscopy-measured HDL-P with cIMT and incident CHD (myocardial infarction, CHD death, and angina, n = 227 events; mean 6.0 years follow-up). All models were adjusted for age, sex, ethnicity, hypertension, and smoking.
HDL-C and HDL-P correlated with each other (ρ = 0.69) and LDL-P (ρ = -0.38, -0.25, respectively, p < 0.05 for all). For (1 SD) higher HDL-C (15 mg/dl) or HDL-P (6.64 μmol/l), cIMT differences were - 26.1 (95% confidence interval [CI]: -34.7 to -17.4) μm and -30.1 (95% CI: -38.8 to - 21.4) μm, and CHD hazard ratios were 0.74 (95% CI: 0.63 to 0.88) and 0.70 (95% CI: 0.59 to 0.82), respectively. Adjusted for each other and LDL-P, HDL-C was no longer associated with cIMT (2.3; 95% CI: - 9.5 to 14.2 μm) or CHD (0.97; 95% CI: 0.77 to 1.22), but HDL-P remained independently associated with cIMT (-22.2; 95% CI: - 33.8 to -10.6 μm) and CHD (0.75; 95% CI: 0.61 to 0.93). Interactions by sex, ethnicity, diabetes, and high-sensitivity C-reactive protein were not significant.
Adjusting for each other and LDL-P substantially attenuated associations of HDL-C, but not HDL-P, with cIMT and CHD. Potential confounding by related lipids or lipoproteins should be carefully considered when evaluating HDL-related risk.
Objectives . The purpose of this study was to test the hypothesis that the reduction of body iron stores by venesection (blood letting) would reduce the susceptibility to oxidation of atherogenic serum lipoproteins.
Design . This is a randomized, controlled cross‐over trial in 14 regularly smoking men with elevated serum ferritin concentration. The study design comprised two 14‐week study periods, with a 14‐week wash‐out period in between, with either blood donations or control.
Setting . The study site was the Research Institute of Public Health, University of Kuopio. Investigators from the Division of Epidemiology, University of Minnesota, Minneapolis, participated in the planning of the study.
Subjects . Fourteen volunteers who were heavy smokers and had previous experience in blood letting were recruited for the study.
Interventions . During the intervention periods, the subjects donated 450 mg (500 mL) of blood three times in 14 weeks.
Main outcome measurements . Oxidation resistance of very low density lipoprotein (VLDL)/low density lipoprotein (LDL) was measured after inducing oxidation with haemin and H 2 O 2 .
Results . Serum ferritin concentration was reduced by 44% [95% confidence interval (CI) 8–82%, P = 0.021] during the venesection periods, the maximal oxidation velocity was decreased by 20% (95% CI 3–30%, P = 0.032), and the lag time to start of oxidation was lengthened (oxidation resistance increased) by 33% (95% CI 1–64%, P = 0.036).
Conclusions . These observations indicate that the reduction of body iron stores by venesection can increase the oxidation resistance of serum VLDL/LDL in regularly smoking men.
Low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol are established risk factors for vascular disease, but lipoprotein particle concentrations may be stronger determinants of risk.
Associations between vascular events and baseline concentrations of cholesterol fractions, apolipoproteins B and A(1), and lipoprotein particles assessed by nuclear magnetic resonance were considered in the Heart Protection Study randomized trial of simvastatin versus placebo (>5000 vascular events during 5.3 years of follow-up among 20 000 participants). Major occlusive coronary events were equally strongly associated with the cholesterol- and particle-based total LDL measures; adjusted hazard ratios per 1-SD-higher level were 1.25 (95% confidence interval [CI], 1.16-1.34) for LDL cholesterol, 1.22 (95% CI, 1.14-1.32) for non-HDL cholesterol, 1.23 (95% CI, 1.15-1.33) for apolipoprotein B, and 1.25 (95% CI, 1.16-1.35) for LDL particle number. Given the total LDL particle number, the distribution between small and large particles did not add predictive value. Associations of these different LDL-related measures were similar with arterial revascularization procedures but much weaker or nonexistent with ischemic stroke and other cardiac events (mainly heart failure). After adjustment for LDL particle number, the hazard ratios for major occlusive coronary event per 1-SD-higher level were 0.91 (95% CI, 0.86-0.96) for HDL cholesterol and 0.89 (95% CI, 0.85-0.93) for HDL particle number. Other cardiac events were inversely associated with total (hazard ratio, 0.84; 95% CI, 0.79-0.90) and small (0.82; 95% CI, 0.76-0.89) HDL particle number but only very weakly associated with HDL cholesterol (0.94; 95% CI, 0.88-1.00).
In a population at 2% average coronary event risk per year, cholesterol, apolipoprotein, and particle measures of LDL were strongly correlated and had similar predictive values for incident major occlusive vascular events. It is unclear whether the associations between HDL particle numbers and other cardiac events represent a causal or reverse-causal effect.
Using a polymeric C18 high-performance liquid chromatographic (HPLC) column, which demonstrated excellent separation selectivity toward carotenoid compounds in an earlier column evaluation, the effects of mobile phase modifier, modifier concentration, and column temperature were investigated. A seven-component carotenoid mixture was used to monitor changes in separation selectivity in response to variations in HPLC conditions. Both acetonitrile and tetrahydrofuran (THF) improved the resolution of echinenone and α-carotene; THF was selected for use as a modifier due to its solvating properties. At concentrations greater than 6% THF, the resolution of lutein and zeaxanthin deteriorated significantly. Temperature was varied from 15 to 35°C in 5°C increments. Resolution of lutein/zeaxanthin and β-cartone/lycopene were better at lower temperatures while echinenone/α-carotene separation improved as temperature increased. An acceptable separation of all seven carotenoids was achieved at 20°C using 5% THF as a mobile phase modifier. Method applicability is demonstrated for serum and food carotenoids.
The cardiomyopathies are heart muscle diseases of primary or secondary origin. Primary cardiomyopathies are often of unknown cause, hence their treatment is limited to general heart failure management. In secondary cardiomyopathies, in contrast, the identification of the underlying cause allows for a more specific, hence effective, approach that, when applied early, may prevent the development of heart failure.
The term iron overload cardiomyopathy (IOC) recently has been introduced to describe a secondary form of cardiomyopathy resulting from the accumulation of iron in the myocardium mainly because of genetically determined disorders of iron metabolism or multiple transfusions.1,2 This condition, although previously overlooked, has lately attracted the attention of investigators because iron overload is, on one hand, a frequently encountered condition, especially in association with certain hematologic conditions, and on the other hand, its accurate identification and effective management have now become possible.
IOC has been recently described as a dilated cardiomyopathy, characterized by left ventricular (LV) remodeling with chamber dilatation and reduced LV ejection fraction (LVEF).1 However, primary hemochromatosis, a genetically determined condition leading to iron overload, is classically categorized as an infiltrative cause of restrictive cardiomyopathy.3 Moreover, secondary hemochromatosis may lead to severe diastolic LV dysfunction in the early stages of the disease, before LVEF is affected.4,5 In the present review, we describe the forms, pathophysiology, and phenotypic expression of IOC, focusing on ventricular geometry and function and describing the early diastolic abnormalities that lead ultimately to heart muscle dysfunction and heart failure. The clinical implications of the condition are also discussed.
Iron overload is the accumulation of excess body iron in different organs as a result of increased intestinal absorption, parenteral administration, or increased dietary intake.6 Besides being a crucial component of hemoglobin with a key role in erythropoiesis, oxygen …
We hypothesized that there is an association between haemochromatosis genotype C282Y/C282Y and/or iron overload and risk of hypertension and/or left ventricular hypertrophy (LVH).
We analysed data from a cross-sectional study of the general population including 8992 individuals from the Copenhagen City Heart Study (CCHS), a follow-up study of 36,480 individuals from the Copenhagen General Population Study (CGPS), and a case-only study of 3815 Scandinavians from the Losartan Intervention For End-point Reduction in Hypertension Genetic Substudy (LIFEGEN) with LVH and hypertension.
In the CCHS, individuals with C282Y/C282Y versus wild type/wild type had an odds ratio for antihypertensive medication use of 4.8 (1.8-13; P = 0.003). In the CGPS, the corresponding hazard ratio was 1.7 (1.0-2.3; P = 0.003). Also, hazard ratios for antihypertensive medication use in the CGPS were 1.6 (1.0-2.6; P = 0.05) for transferrin saturation > or =80% vs. <50%, and 2.3 (1.3-4.2; P = 0.005) for C282Y/C282Y + transferrin saturation > or =80% vs. wild type/wild type + transferrin saturation <50%. These results were most pronounced in men above 55 years of age. We did not find any association between C282Y/C282Y or iron overload and LVH or hypertension (measured as blood pressure at a single occasion or continuous blood pressure), or LVH with hypertension in the CCHS or with severity of LVH in LIFEGEN.
We found that haemochromatosis genotype C282Y/C282Y and extremely elevated transferrin saturation either separately or combined were associated with increased risk of antihypertensive medication use. Therefore, testing for haemochromatosis genotype C282Y/C282Y and extreme transferrin saturation could be considered in patients with essential hypertension.
Several abnormalities in the immune status of patients with hereditary haemochromatosis (HH) have been reported, suggesting an imbalance in their immune function. This may include persistent production of, or exposure to, altered immune signalling contributing to the pathogenesis of this disorder. Adhesion molecules L-, E- and P-Selectin, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) are some of the major regulators of the immune processes and altered levels of these proteins have been found in pathological states including cardiovascular diseases, arthritis and liver cancer. The aim of this study was to assess L-, E- and P-Selectin, ICAM-1 and VCAM-1 expression in patients with HH and correlate these results with HFE mutation status and iron indexes. A total of 139 subjects were diagnosed with HH (C282Y homozygotes = 87, C282Y/H63D = 26 heterozygotes, H63D homozygotes = 26), 27 healthy control subjects with no HFE mutation (N/N), 18 normal subjects heterozygous for the H63D mutation served as age-sex-matched controls. We observed a significant decrease in L-selectin (P = 0.0002) and increased E-selectin and ICAM-1 (P = 0.0006 and P = 0.0059) expression in HH patients compared with healthy controls. This study observes for the first time that an altered adhesion molecules profile occurs in patients with HH that is associated with specific HFE genetic component for iron overload, suggesting that differential expression of adhesion molecules may play a role in the pathogenesis of HH.
Whether mutations in the hemochromatosis (HFE) gene increase cardiovascular disease risk is still undetermined. The main reason is the low frequency of the mutations, in particular of the compound C282Y/H63D genotype. We combined the data of 11 observational studies for an individual patient data meta-analysis.
Individual patient data were obtained from published as well as unpublished studies that had information available on the C282Y mutation as well as the H63D mutation in relation to coronary heart disease risk. Individual records were provided on each of the 53 880 participants in 11 studies. In total, 10 541 patients with coronary events were documented, of whom 5724 had an acute myocardial infarction. The crude and adjusted association between HFE genotypes and coronary events was examined by logistic regression analysis. We explored potential effect modification of the association between traditional cardiovascular risk factors and coronary events by HFE genotypes. After full adjustment, the odds ratio for coronary heart disease was 1.12 (95% CI, 0.92 to 1.37) for subjects with the compound heterozygous (C282Y/H63D) genotype relative to those with the wild-type/wild-type genotype. The odds ratios for C282Y/C282Y, C282Y/wild-type, H63D/H63D, and H63D/wild-type were 0.78 (95% CI, 0.49 to 1.26), 0.98 (95% CI, 0.90 to 1.07), 1.16 (95% CI, 0.97 to 1.38), and 1.07 (95% CI, 1.00 to 1.14), respectively. There was no evidence for effect modification.
The results of this large individual patient data meta-analysis do not support the view that HFE gene mutations are associated with an increased risk of coronary heart disease or acute myocardial infarction.
Little is known about the early mechanisms mediating left ventricular (LV) diastolic dysfunction in patients with hereditary hemochromatosis (HH). However, the increased oxidative stress related to iron overload may be involved in this process, and strain rate (SR), a sensitive echocardiography-derived measure of diastolic function, may detect such changes.
we evaluated the relationship between left ventricular diastolic function measured with tissue Doppler SR and oxidative stress in asymptomatic HH subjects and control normal subjects.
Ninety-four consecutive visits of 43 HH subjects, age 30-74 (50 +/- 10, mean +/- SD), and 37 consecutive visits of 21 normal volunteers, age 30-63 (48 +/- 8), were evaluated over a 3-year period. SR was obtained from the basal septum in apical four-chamber views. All patients had confirmed C282Y homozygosity, a documented history of iron overload, and were New York Heart Association functional class I. Normal volunteers lacked HFE gene mutations causing HH.
In the HH subjects, the SR demonstrated moderate but significant correlations with biomarkers of oxidative stress; however, no correlations were noted in normal subjects. The biomarkers of iron overload per se did not show significant correlations with the SR.
Although our study was limited by the relatively small subject number, these results suggest that a possible role of oxidative stress to affect LV diastolic function in asymptomatic HH subjects and SR imaging may be a sensitive measure to detect that effect.
Serum levels of vitamin A, its specific carrier protein retinol-binding protein (RBP), and zinc were determined in 34 cases of idiopathic hemochromatosis, 33 cases of alcoholic cirrhosis, 10 cases of non-alcoholic cirrhosis, and in 35 normal controls. In both alcoholic and non-alcoholic cirrhosis, vitamin A and RBP levels were very significantly reduced, whereas a significantly low zinc was observed only in the alcoholic cirrhosis group. In idiopathic hemochromatosis, vitamin A values were significantly lower compared to normals, whereas serum RBP levels were normal and serum zinc was very close to that of the controls. A significant correlation was found between vitamin A and RBP levels in the entire group of 112 patients. These results, (1) in alcoholic and non-alcoholic cirrhosis, confirm a dramatic vitamin A deficiency and the major role played by decreased RBP, but tend to deemphasize the possible role of zinc deficiency; (2) in idiopathic hemochromatosis, affirm a significant serum vitamin A deficiency supposedly by a different mechanism from that of alcoholic cirrhosis since in idiopathic hemochromatosis plasma RBP levels are normal. The role of this vitamin A disorder should be considered in the interpretation of clinical signs of idiopathic hemochromatosis such as ichthyosis and visual disorders.
Vitamin C status was studied, by means of leucocyte ascorbic acid concentrations, in 67 cases of idiopathic hemochromatosis subdivided into 44 untreated and 25 treated cases (2 patients belonging to both subgroups) and compared to 31 normal subjects and 37 alcoholic cirrhosis patients. The control groups exhibited the following mean levels (+/- SEM): 34.4 +/- 1.9 microgram/10(8) WBC in normals and 22.0 +/- 1.8 microgram/10(8) WBC in alcoholic cirrhosis. In idiopathic hemochromatosis the mean levels were: for the untreated group 19.5 +/- 1.7 microgram/10(8) WBC and for the treated group 34.3 +/- 2.3 microgram/10(8) WBC. These results (1) affirm an important vitamin C deficiency in the untreated disease; (2) suggest that iron overload is the main causal factor in view of the striking difference--to date unreported--between untreated and treated cases of idiopathic hemochromatosis. Besides its possible theoretical interests, this vitamin C deficiency is responsible in idiopathic hemochromatosis for a significant underestimation of the desferrioxamine-induced urinary iron excretion.
Endothelial dysfunction is an early event in experimental studies of atherogenesis, preceding formation of plaques. We have devised a non-invasive method for testing endothelial function, to find out whether abnormalities are present in symptom-free children and young adults at high risk of atherosclerosis. With high-resolution ultrasound, we measured the diameter of the superficial femoral and brachial arteries at rest, during reactive hyperaemia (with increased flow causing endothelium-dependent dilatation), and after sublingual glyceryl trinitrate (GTN; causing endothelium-independent dilatation) in 100 subjects--50 controls without vascular risk factors (aged 8-57 years), 20 cigarette smokers (aged 17-62 years), 10 children with familial hypercholesterolaemia (FH; aged 8-16 years), and 20 patients with established coronary artery disease (CAD). Adequate scans were obtained in all but 6 cases. Flow-mediated dilatation was observed in arteries from all control subjects. Dilatation was inversely related to baseline vessel diameter (r = -0.81, p < 0.0001); in arteries of 6.0 mm or less, mean dilatation was 10 (SE 2)%. In smokers, FH children, and adults with CAD, flow-mediated dilatation was much reduced or absent (p < 0.001 for comparison with each relevant control group). Dilatation in response to GTN was present in all groups. Endothelial dysfunction is present in children and adults with risk factors for atherosclerosis, such as smoking and hypercholesterolaemia, before anatomical evidence of plaque formation in the arteries studied. This may be an important early event in atherogenesis.
Iron can induce lipid peroxidation in vitro and in vivo in humans and has promoted ischemic myocardial injury in experimental animals. We tested the hypothesis that high serum ferritin concentration and high dietary iron intake are associated with an excess risk of acute myocardial infarction.
Randomly selected men (n = 1,931), aged 42, 48, 54, or 60 years, who had no symptomatic coronary heart disease at entry, were examined in the Kuopio Ischaemic Heart Disease Risk Factor Study (KIHD) in Eastern Finland between 1984 and 1989. Fifty-one of these men experienced an acute myocardial infarction during an average follow-up of 3 years. On the basis of a Cox proportional hazards model adjusting for age, examination year, cigarette pack-years, ischemic ECG in exercise test, maximal oxygen uptake, systolic blood pressure, blood glucose, serum copper, blood leukocyte count, and serum high density lipoprotein cholesterol, apolipoprotein B, and triglyceride concentrations, men with serum ferritin greater than or equal to 200 micrograms/l had a 2.2-fold (95% CI, 1.2-4.0; p less than 0.01) risk factor-adjusted risk of acute myocardial infarction compared with men with a lower serum ferritin. An elevated serum ferritin was a strong risk factor for acute myocardial infarction in all multivariate models. This association was stronger in men with serum low density lipoprotein cholesterol concentration of 5.0 mmol/l (193 mg/dl) or more than in others. Also, dietary iron intake had a significant association with the disease risk in a Cox model with the same covariates.
Our data suggest that a high stored iron level, as assessed by elevated serum ferritin concentration, is a risk factor for coronary heart disease.
The programming of the Cobas-Bio centrifugal analyzer for kinetic tests of transketolase, glutathione reductase and aspartate amino-transferase is described. The results obtained in a population of 200 healthy people of both sexes are reported.
A possible association between body iron stores, measured as serum ferritin, and carotid arterial intima-media thickening was investigated in the Atherosclerosis Risk in Communities Study during 1990-1992 using a matched case-control design. For a 143-micrograms/liter greater serum ferritin concentration (the interquartile range), the odds ratio for cases with carotid intima-media thickening versus controls was 1.12 (95% confidence interval 0.97-1.30). However, there was no association (odds ratio = 1.00) after adjusting for major cardiovascular risk factors. This analysis of carotid arterial intima-media thickening, a measure of early atherosclerosis, in relation to serum ferritin does not support the hypothesis that increased body iron stores increase the risk of atherosclerotic cardiovascular disease.
The purpose of this study was to test the hypothesis that the reduction of body iron stores by venesection (blood letting) would reduce the susceptibility to oxidation of atherogenic serum lipoproteins.
This is a randomized, controlled cross-over trial in 14 regularly smoking men with elevated serum ferritin concentration. The study design comprised two 14-week study periods, with a 14-week wash-out period in between, with either blood donations or control.
The study site was the Research Institute of Public Health, University of Kuopio. Investigators from the Division of Epidemiology, University of Minnesota, Minneapolis, participated in the planning of the study.
Fourteen volunteers who were heavy smokers and had previous experience in blood letting were recruited for the study.
During the intervention periods, the subjects donated 450 mg (500 mL) of blood three times in 14 weeks.
Oxidation resistance of very low density lipoprotein (VLDL)/low density lipoprotein (LDL) was measured after inducing oxidation with haemin and H2O2.
Serum ferritin concentration was reduced by 44% [95% confidence interval (CI) 8-82%, P = 0.021] during the venesection periods, the maximal oxidation velocity was decreased by 20% (95% CI 3-30%, P = 0.032), and the lag time to start of oxidation was lengthened (oxidation resistance increased) by 33% (95% CI 1-64%, P = 0.036).
These observations indicate that the reduction of body iron stores by venesection can increase the oxidation resistance of serum VLDL/LDL in regularly smoking men.
High body iron stores have been proposed as a risk factor for advanced atherosclerosis. We investigated the prevalence of early atherosclerotic changes, and their relation to conventional CHD risk factors and body iron status. A cross-sectional study was carried out in 206 men aged 50 to 60 years (6% random population sample). Intima-media thickness (IMT) of the carotid artery was evaluated with high-resolution B-mode ultrasonography. Statistical analyses were performed separately for men with and without cardiovascular disease (CVD). Among all the study participants, 6.6% had IMT > 1.3 mm in the common carotid artery, whereas 53.8% had IMT > 1.5 mm in the carotid bifurcation. Respective values were 4.8% and 46.8% for those without CVD, and 8.5% and 62.2% for those with CVD. Mean IMT in the carotid bifurcation, the predilection site for atherosclerosis, was 1.85 mm (95% CI 1.72; 1.98) in the men with CVD, as compared to 1.65 mm (95% CI 1.56; 1.73) in the men free of CVD. Serum LDL cholesterol (beta = 0.26), saturated fat intake (beta = 0.20), blood haemoglobin (beta = -0.29), systolic blood pressure (beta = 0.21) and smoking (beta = 0.19), jointly explained 23% of the variance in the carotid bifurcation IMT in the men without CVD. Neither serum ferritin, transferrin nor dietary iron levels were associated with carotid bifurcation atherosclerosis. On the other hand, in the men with CVD, age (beta = 0.34) and physical activity (beta = -0.25) jointly explained 16.5% of the IMT variance in the carotid bifurcation.(ABSTRACT TRUNCATED AT 250 WORDS)
Hereditary haemochromatosis is characterised by iron overload that may lead to tissue damage. Free iron is a potent promoter of hydroxyl radical formation that can cause increased lipid peroxidation and depletion of chain-breaking antioxidants. We have therefore assessed lipid peroxidation and antioxidant status in 15 subjects with hereditary haemochromatosis and age/sex matched controls. Subjects with haemochromatosis had increased serum iron (24.8 (19.1-30.5) vs. 17.8 (16.1-19.5) mumol/l, p = 0.021) and % saturation (51.8 (42.0-61.6) vs. 38.1 (32.8-44.0), p = 0.025). Thiobarbituric acid reactive substances (TBARS), a marker of lipid peroxidation, were increased in haemochromatosis (0.59 (0.48-0.70) vs. 0.46 (0.21-0.71) mumol/l, p = 0.045), and there were decreased levels of the chain-breaking antioxidants alpha-tocopherol (5.91 (5.17-6.60) vs. 7.24 (6.49-7.80) mumol/mmol cholesterol, p = 0.001), ascorbate (51.3 (33.7-69.0) vs. 89.1 (65.3-112.9), p = 0.013), and retinol (1.78 (1.46-2.10) vs. 2.46 (2.22-2.70) mumol/l, p = 0.001). Patients with hereditary haemochromatosis have reduced levels of antioxidant vitamins, and nutritional antioxidant supplementation may represent a novel approach to preventing tissue damage. However, the use of vitamin C may be deleterious in this setting as ascorbate can have prooxidant effects in the presence of iron overload.
Atherosclerosis, the principal cause of heart attack, stroke and gangrene of the extremities, is responsible for 50% of all mortality in the USA, Europe and Japan. The lesions result from an excessive, inflammatory-fibroproliferative response to various forms of insult to the endothelium and smooth muscle of the artery wall. A large number of growth factors, cytokines and vasoregulatory molecules participate in this process. Our ability to control the expression of genes encoding these molecules and to target specific cell types provides opportunities to develop new diagnostic and therapeutic agents to induce the regression of the lesions and, possibly, to prevent their formation.
The course of hereditary hemochromatosis may depend on the degree of iron overload and the time of therapeutic intervention. This analysis evaluates the impact of early diagnosis and iron removal on survival and complications in hereditary hemochromatosis.
A Cohort of 251 patients with hemochromatosis was followed up for 14.1 +/- 6.8 years.
Survival was reduced in the total group of patients when compared with a matched normal population. Survival in noncirrhotic and nondiabetic patients and in patients diagnosed between 1982 and 1991 was identical with rates expected. Survival was reduced in patients with severe iron overload vs. those with less severe overload. The percentage of early diagnoses increased threefold between 1947 and 1969 to that between 1970 and 1981; there was only a further 20%-25% increase in the last decade. Deaths caused by liver cancer, cardiomyopathy, liver cirrhosis, and diabetes mellitus were increased as compared with expected rates. Liver cancers were associated with cirrhosis and amount of mobilizable iron but not with hepatitis B or C markers.
Prognosis of hemochromatosis and most of its complications, including liver cancer, depend on the amount and duration of iron excess. Early diagnosis and therapy largely prevent the adverse consequences of iron overload.
Genetic hemochromatosis (GH) is associated with excess iron deposition in hepatocytes, which results in progressive hepatic injury. The pathogenesis of hepatic injury in GH is poorly understood. In this study, we found enhanced oxidative stress in patients with GH, as evidenced by hepatic malondialdehyde (MDA)-protein adducts and by increased oxidatively modified serum proteins. MDA-lysine epitopes and oxidatively modified serum proteins, as well as immunoglobulin G autoantibodies against MDA-lysine epitopes, were increased in untreated GH patients and to a lesser extent in GH heterozygotes compared with normal individuals. These markers of ongoing oxidative stress decreased with phlebotomy treatment in GH patients. In addition, TGF-beta1 colocalized with hepatic iron and MDA protein adducts in hepatocytes and sinusoidal cells of hepatic acinar zone 1 and normalized after iron removal. Our data suggest that iron overload increases both lipid peroxidation and TGF-beta1 expression, which together could promote hepatic injury and fibrogenesis.
Fe2+ released from tissue iron stores may accelerate lipid peroxidation by virtue of its pro-oxidant properties and thus promote early atherogenesis.
The present prospective survey addresses the potential association between serum ferritin concentrations and the 5-year progression of carotid atherosclerosis as assessed by ultrasonographic follow-up evaluations. The study population comprises a random sample of 826 men and women 40 to 79 years old. Serum ferritin was one of the strongest risk predictors of overall progression of atherosclerosis. The main part of this association appeared to act through modification of the atherogenic potential of LDL cholesterol (OR [95% CI] for a 1-SD unit increase in ferritin at LDL levels of 2.5, 3.6, and 4.9 mmol/L: 1.55 [1.30 to 1.85], 1.77 [1.40 to 2.24], and 2.05 [1.50 to 2.80]; P=.0012 for effect modification). Changes in iron stores during the follow-up period modified atherosclerosis risk, in that a lowering was beneficial and further iron accumulation exerted unfavorable effects. All these findings applied equally to incident atherosclerosis and the extension of preexisting atherosclerotic lesions. The significance of prominent iron stores in the development of carotid stenosis was clearly less pronounced. Finally, ferritin and LDL cholesterol showed a synergistic association with incident cardiovascular disease and death (n=59).
The present study provided strong epidemiological evidence for a role of iron stores in early atherogenesis and suggests promotion of lipid peroxidation as the main underlying pathomechanism. This hypothesis could in part explain the sex difference in atherosclerotic vascular disease.
Epidemiological evidence concerning the role of iron, a lipid peroxidation catalyst, in coronary heart disease (CHD) is inconsistent. We investigated the association of the concentration ratio of serum transferrin receptor to serum ferritin (TfR/ferritin), a state-of-the-art measurement of body iron stores, with the risk of acute myocardial infarction (AMI) in a prospective nested case-control study in men from eastern Finland.
Transferrin receptor assays were carried out for 99 men who had an AMI during an average 6.4 years of follow-up and 98 control men. Both the cases and the controls were nested from the Kuopio Ischemic Heart Disease Risk Factor Study (KIHD) cohort of 1931 men who had no clinical CHD at the baseline study. The controls were matched for age, examination year, and residence. AMIs were registered prospectively. Soluble transferrin receptors were measured by immunoenzymometric assay and ferritin concentration by radioimmunoassay from frozen baseline serum samples. The mean TfR/ferritin ratio was 15.1 (SE, 2.0) among cases and 21.3 (SE, 2.2) among controls (P=.035 for difference). In logistic regression models adjusting for other strongest risk factors for AMI and indicators of inflammation and alcohol intake, men in the lowest and second lowest thirds of the TfR/ferritin ratio had a 2.9-fold (95% CI, 1.3 to 6.6, P=.011) and 2.0-fold (0.9 to 4.2, P=.081) risk of AMI compared with men in the highest third (P=.010 for trend).
These data show an association between increased body iron stores and excess risk of AMI, confirming previous epidemiological findings.
Lipid peroxidation results in the formation of conjugated dienes, lipid hydroperoxides and degradation products such as alkanes, aldehydes and isoprostanes. The approach to the quantitative assessment of lipid peroxidation depends on whether the samples involve complex biological material obtained in vivo, or whether the samples involve relatively simple mixtures obtained in vitro. Samples obtained in vivo contain a large number of products which themselves may undergo metabolism. The measurement of conjugated diene formation is generally applied as a dynamic quantitation e.g. during the oxidation of LDL, and is not generally applied to samples obtained in vivo. Lipid hydroperoxides readily decompose, but can be measured directly and indirectly by a variety of techniques. The measurement of MDA by the TBAR assay is non-specific, and is generally poor when applied to biological samples. More recent assays based on the measurement of MDA or HNE-lysine adducts are likely to be more applicable to biological samples, since adducts of these reactive aldehydes are relatively stable. The discovery of the isoprostanes as lipid peroxidation products which can be measured by gas chromatography mass spectrometry or immunoassay has opened a new avenue by which to quantify lipid peroxidation in vivo, and will be discussed in detail.
Large artery damage is a major contributory factor to cardiovascular morbidity and mortality of patients with hypertension. Pulse wave velocity (PWV), a classic evaluation of arterial distensibility, has never been ascertained as a cardiovascular risk marker. To determine the factors influencing aortic PWV and the potential predictor role of this measurement, we studied a cohort of 710 patients with essential hypertension. Atherosclerosis alterations (AA) were defined on the basis of clinical events. Calculation of cardiovascular risks, by use of Framingham equations, was performed in subjects without AA. PWV was higher in the presence of AA (14.9+/-4.0 versus 12.4+/-2.6 m/s, P<0.0001), even after adjustments on confounding factors and was the first determinant (P<0.0001) of the extent of atherosclerosis assessed as the sum of the atherosclerotic sites. In patients without AA, all cardiovascular risks increased constantly with PWV. Furthermore, at a given age, aortic PWV was the best predictor of cardiovascular mortality. The odds ratio of being in a high cardiovascular mortality risk group (>5% for 10 years) for patients in the upper quartile of PWV was 7.1 (95% confidence intervals 4.5 to 11.3). The presence of a PWV >13 m/s, taken alone, appeared as a strong predictor of cardiovascular mortality with high performance values. This study shows that aortic PWV is strongly associated with the presence and extent of atherosclerosis and constitutes a forceful marker and predictor of cardiovascular risk in hypertensive patients.
The aim of this review was to bring together results obtained from studies on different aspects of HDL as related to CHD and atherosclerosis. As atherosclerosis is a multistep process, the various components of HDL can intervene at different stages, such as induction of monocyte adhesion molecules, prevention of LDL modification and removal of excess cholesterol by reverse cholesterol transport. Transgenic technology has provided a model for atherosclerosis, and permitted evaluation of the contributions of different HDL components towards the global effect. The availability of apo AIV transgenic mice amplified the results obtained from apo AI overexpressors with respect to prevention of atherosclerosis. Prevention of atherosclerosis in apo E deficient mice by relatively small amounts of macrophage derived apo E may open new possibilities for therapeutic intervention. Contrary to early notions, increased plasma levels of CETP, even in the presence of low but functionally normal HDL, were atheroprotective. The extent to which paraoxonase and apo J participate in prevention of human atherosclerosis needs further evaluation. The findings that LCAT overexpression in rabbits was atheroprotective in contrast to increase in atherosclerosis in h LCAT tg mice, which was only partially corrected by CETP expression, call for some caution in the extrapolation of results from transgenic animals to humans. The important discovery of SR-BI as the receptor for selective uptake of CE from HDL revived interest in the clearance of CE from plasma. This pathway supplies also the vital precursor for steroidogenesis in adrenals and gonads and was shown to be dependent on apo AI.
Background —Homozygosity for a relatively common Cys282Tyr mutation of the human hemochromatosis-associated ( HFE ) gene was recently found to account for most cases of hereditary hemochromatosis. Because excess iron has been postulated to enhance risk of vascular disease, we studied whether occurrence of this mutation was associated with increased risk of first acute myocardial infarction in healthy middle-aged men in a prospective cohort study.
Methods and Results —Study subjects were the 1150 participants in the population-based Kuopio Ischemic Heart Disease Risk Factor Study (KIHD), aged 42, 48, 54, or 60 years at baseline, who had no coronary heart disease at baseline and for whom a DNA sample was available. Information about myocardial infarctions was collected prospectively by use of FINMONICA (FINnish MONItoring of trends and determinants in CArdiovascular disease study) and hospital data. Events were classified by MONICA (MONItoring of trends and determinants in CArdiovascular disease study) diagnostic criteria. The HFE Cys282Tyr mutation was assayed by a solid-phase minisequencing technique. One subject was homozygous and 76 individuals were heterozygous for the HFE Cys282Tyr mutation (6.7%). During a mean follow-up of 9 years, 8 (10.4%) of 77 carriers and 60 (5.6%) of 1073 noncarriers experienced an acute myocardial infarction. In a Cox proportional hazards model allowing for the other strongest risk factors, the carriers had a 2.3-fold (95% CI 1.1 to 4.8; P =0.03) risk of acute myocardial infarction compared with noncarriers.
Conclusions —Male carriers of the common hemochromatosis gene mutation are at 2-fold risk for first acute myocardial infarction compared with noncarriers.
Serum ferritin and heterozygosity for the C282Y mutation of the hemochromatosis gene have both been associated with an increased risk of cardiovascular events. The purpose of the study was to test whether either is a risk predictor for asymptomatic carotid atherosclerosis.
We assessed carotid intima-media wall thickness (IMT) and focal plaque formation by high-resolution B-mode ultrasound, conventional risk factors, serum ferritin levels, and the C282Y mutation of the hemochromatosis gene in a randomly selected community population of 1098 subjects (545 women and 553 men) aged 27 to 77 years.
After adjustment for conventional risk factors, serum ferritin was not associated with carotid mean IMT. Women with ferritin values over the first quartile (>34 microg/L) had an adjusted odds ratio of 2.1 (95% CI, 1. 3 to 3.4; P:=0.0016) for carotid plaque compared with the first quartile. Ferritin was not associated with carotid plaque in men. Subjects who were heterozygous for the C282Y mutation constituted 11. 4% of the population, and there was no independent association of this genotype with either carotid IMT or focal plaque formation.
We conclude that in our community population, C282Y genotype status was not a risk predictor for either carotid mean IMT or plaque formation. Serum ferritin values in women were independently associated with carotid plaque.
According to some authors blood donors have a lower risk of cardiovascular incidents. This may be associated with the risk of cardiovascular disease reported by some authors, as well as with the oxidative changes caused by iron. The aim of this study was to determine, what happens to some of the factors contributing to atherosclerosis after the lowering of body iron. Blood was drawn from 23 healthy males after overnight fasting and the parameters described below determined. These persons donated blood (500 ml) on three occasions with 6 weeks intervals. Six to eight weeks after the third and final donation, blood was again drawn after overnight fasting and the following parameters measured for the second time: various parameters of body iron; lipid profile; anti-oxidants; and oxidative parameters of low density lipoprotein (LDL). Blood donation has various beneficial effects, such as increasing high density lipoprotein (HDL) and apoA; a higher oxidative potential of LDL; a lower level of LDL peroxidation resulting in a LDL particle with a higher oxidative potential, and a higher NO(3) concentration. We conclude that blood donation, and thereby a lowered body iron concentration, is an effective way to increase the oxidative potential of LDL, as well as the HDL and apoA concentrations.