|Year : 2019 | Volume
| Issue : 8 | Page : 1120-1125
Aortic stiffness in patients with wilson's disease
AS Gurbuz1, S Ozturk2, SC Efe3, K Demir4
1 Department of Cardiology, Necmettin Erbakan University, Meram Faculty of Medicine, Konya, Turkey
2 Department of Cardiology, Haseki Training and Research Hospital, Istanbul, Turkey
3 Department of Cardiology, Istanbul Training and Research Hospital, Istanbul, Turkey
4 Department of Gastroenterology, Istanbul University, İstanbul Faculty of Medicine, Istanbul, Turkey
|Date of Acceptance||12-Apr-2019|
|Date of Web Publication||14-Aug-2019|
Dr. A S Gurbuz
Department of Cardiology, Necmettin Erbakan University, Meram Faculty of Medicine, Meram, Konya - 42080
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Aim: Wilson's disease (WD) presents with different phenotypes. Neurologic and liver involvement in WD are well documented. Few reports demonstrated cardiac and vascular involvement. Several studies showed an association between serum copper levels and atherosclerosis. Although WD is the prototype disease of copper metabolism, atherosclerosis has not been studied yet. The aim of this study is to assess aortic stiffness in WD. Materials and Methods: Aortic pulse wave velocity (PWV), augmentation pressure (AP), augmentation index (AIx), central aortic systolic, diastolic, mean, and pulse pressures were measured using SphygmoCor (AtCor Medical) device in 32 patients with WD and 24 healthy controls. Results: Patients with WD and healthy controls were similar in terms of age sex, body mass index (BMI), and liver and kiney functions. However, patients with WD were anemic and thrombocytopenic. Echocardiographic parameters including left ventricular, atrial dimensions, and systolic and diastolic functions were similar between two groups. Patients with WD and healthy controls were compared. Baseline characteristics including age, sex, and BMI did not differ between groups. Central aortic systolic, diastolic, mean, and pulse pressures were similar between the groups. AP, AIx, and PWV did not differ between groups as well. Conclusion: Aortic stiffness in WD was similar in healthy controls.
Keywords: Aortic stiffness, copper metabolism, Wilson's disease
|How to cite this article:|
Gurbuz A S, Ozturk S, Efe S C, Demir K. Aortic stiffness in patients with wilson's disease. Niger J Clin Pract 2019;22:1120-5
| Introduction|| |
Wilson's disease (WD) is an autosomal recessive disease which is characterized by copper deposition in basal ganglia, liver, kidney, cornea, bone, and myocardium. Since genotype and phenotype relationship is complex, severity and involvement of different organs vary. Although neurologic and liver involvement are well studied and documented, cardiovascular involvement still remains to be clarified. The myocardial copper deposition was first described in a few cases., Latter, a larger postmortem study not only confirmed the myocardial involvement but also described a patient with premature atherosclerosis of left main coronary artery.
Several studies showed an association between serum copper levels and atherosclerosis., Although some studies found higher levels of serum copper in atherosclerotic patients, others found lower levels. Despite controversial reports, the Ludwigshafen Risk and Cardiovascular Health Study showed that elevated concentrations of both copper and ceruloplasmin are independently associated with cardiovascular and all-cause mortality.
Pulse wave velocity (PWV) and augmentation index (AIx) are measures of aortic stiffness and they are closely related to cardiovascular wellness. Large studies showed association of these indices with the atherosclerotic process, and thus they are potential predictors of cardiovascular mortality. WD is the prototype disease of copper metabolism which classically presents with low serum levels of ceruloplasmin and high serum levels of free (nonceruloplasmin-bound) copper. However, atherosclerosis – which may be affected by altered copper metabolism in WD – has not been studied yet. We aimed to assess aortic stiffness indices in WD.
| Materials and Methods|| |
The study included 32 patients with WD and 24 healthy control subjects. Diagnosis of WD was established by a gastroenterologist depending on international criteria including serum ceruloplasmin levels and urine copper levels. All diagnosis was confirmed with a liver biopsy. Neurologic involvement was assessed by a neurologist. Cranial magnetic resonance imaging was obtained in all patients. Patients with severe hepatic disease/cirrhosis, diabetes mellitus, arterial hypertension, coronary artery disease, and rheumatologic disease were excluded from the study. Smokers were not admitted to the study. Healthy subjects with age and gender similar to the patient group were included in the study as a control group. In the control group, no patients had exclusion criteria of the study. The study was approved by the local ethics committee.
The same experienced echocardiographer, who was blinded to the study, examined all subjects; 1–5 MHz X5-1 transducer (iE33; Philips Healthcare, Inc., Andover, MA, USA) was used for standard echocardiographic evaluation. Left atrial, left ventricle end-diastolic, and end-systolic diameters were measured from parasternal long-axis view using M-mode. Left ventricle ejection fraction was calculated according to Simpson's formula. Mitral inflow velocities were measured by PW Doppler.
Aortic PWV and AIx measurement, SphygmoCor device
All participants were asked to avoid intake of caffeinated, alcoholic beverages, and other stimulants within 3 h and strenuous exercise 24 h before measurement. The participants had rest in the supine position for 10 min before measurement at a room temperature of 20°C–23°C between 09:00 and 12:00 hours.
Aortic PWV was measured using SphygmoCor (AtCor Medical, Sydney, Australia) device. By this method, first carotid and then femoral pulse wave were examined with simultaneous electrocardiography (ECG). Time elapsed between the beginning of R wave and the beginning of pulse wave was calculated automatically on ECG. Then the difference of time measured for femoral and carotid artery was calculated automatically by the device. This difference shows the time elapsed of the propagation of the pulse wave from the carotid artery to the femoral artery. Thereafter, the distance is measured on the body surface between the spots where the measurements for carotid and femoral arteries were performed. After this, measurement values were set on the device and aortic PWV was automatically calculated as meters/second [Figure 1].
AIx was measured noninvasively by SphygmoCor device. Pressure waveforms on radial artery were recorded by high-fidelity applanation tonometry (Millar Instruments, Houston, TX, USA). Central aortic waveform was automatically acquired by SphygmoCor device. Pulse pressure (PP) and augmentation pressure (AP) were calculated on this wave form automatically. AIx was obtained by dividing AP by PP [Figure 2]. Since AIx is affected by heart rate, heart rate was normalized to 75 pulses/min. All measurements were performed by the same cardiologist, blinded to the study and patients, who has experience with the device.
|Figure 2: Augmentation index measured from radial artery with an applanation tonometry on SphygmoCor device|
Click here to view
Data management and analysis were performed using IBM SPSS Statistics 16.0 (SPSS, Chicago, IL, USA) software. Data are presented as mean ± standard deviation for continuous variables and as percentages for categorical variables. Normal distribution was analyzed using Kolmogorov–Smirnov test. Categorical variables were compared using Chi-square or Fisher's exact test as appropriate. Student t-test or Mann-Whitney U test was used to compare continuous variables as appropriate. P value less than 0.05 was regarded as significant.
| Results|| |
Patients with WD and healthy controls were similar in terms of age sex, body mass index (BMI), and liver and kidney functions. However, patients with WD were anemic and thrombocytopenic [Table 1]. Echocardiographic parameters including left ventricular, atrial dimensions, and systolic and diastolic functions were similar between two groups. Patients with WD and healthy controls were compared. Baseline characteristics including age, sex, and BMI did not differ between groups. Central aortic systolic, diastolic, mean, and pulse pressures were similar between the three groups. AP, AIx, and PWV did not differ between groups as well [Table 2].
|Table 2: Medication, echocardiographic, and aortic stiffness parameters of subjects|
Click here to view
| Discussion|| |
Our study showed that for the first time, aortic stiffness is not increased in WD. We investigated both cardiac and aortic functions which enabled thorough examination of the cardiovascular system. Up to now, knowledge about atherosclerosis in WD was restricted to case reports and case series. Although these valuable reports raised suspicion, there was lack of objective approach for assessment of atherosclerosis. PWV is not only widely used for research purposes but also it was recently recommended by European guideline for evaluating atherosclerosis risk. Besides aortic stiffness, we also demonstrated preserved cardiac structures and functions contrary to previous studies which asserted significant myocadial involvement in WD. Since the primary aim of this study is to investigate atherosclerosis, we did not further evaluate cardiac functions such as deformation parameters which is another research issue.
International study group for Wilson's disease (ISGW) classified WD into H1, H2, and N1 phenotypes depending on initial clinical manifestation. WD was classified into two phenotypes according to chronic organ damage: uncomplicated chronic liver disease of WD and chronic liver disease complicated with neurological disease of Wilson. In our study, we preferred the latter terminology since cardiovascular disease is a chronic disorder. A previous study showed prolonged QTc interval in patients with Neuorologic Wilson's Disease (NWD) compared with non-NWD. Altered QTc interval might be more related to cardiac autonomic dysfunction in patients with NWD. Myocardial involvement in patients with WD, assessed with ECG indices, was not present in the aforementioned study. However, the atherosclerotic process in WD remained to be clarified. To our best knowledge, this study is the only research investigating atherosclerotic process with objective measures in WD.
The largest cohort up to now searched for cardiac myopathy in 463 patients with WD. This study concluded that WD was associated with both systolic and diastolic heart failure (HF). Contrary to this study, systolic and diastolic functions in WD were preserved in our study. The mean age was 49 years, and 15% of patients were cirrhotic, whereas only 0.4% of control patients were cirrhotic in this cohort. In addition, hypertension, obesity, kidney disease, smoking, and coronary artery disease were more frequent in patients with WD. Cirrhosis might be the underlying cause of high frequency of comorbidities including coronary artery disease and HF. Cirrhotic cardiomyopathy might interfere with the results. Additionally, some studies reported possible association between cirrhosis and atherosclerosis, which may cause greater aortic stiffness in cirrhotic patients. In our noncirrhotic patient population, aortic stiffness parameters did not seem to worsen in patients with WD.
Copper takes part in redox reactions. Oxidative reactions are dependent on copper. About 90% of copper in serum is bound to ceruloplasmin. Several studies demonstrated that ceruloplasmin levels may be an indicator of oxidative stres. On the other hand, several studies showed an association between oxidative stress and atherosclerosis. Copper caused vascular inflammation and neointima formation in rat carotid arteries. A cross-sectional study found a relationship between serum copper level and increased aortic stiffness in 737 apparently healthy subjects. Moreover, ceruloplasmin may be a source of redox active copper which may consequently cause oxidation of low-density lipoprotein (LDL) particles. Lee MJ et al. showed that increased ceruloplasmin was independently related to increased aortic stiffness in men with type 2 diabetes. Several studies proposed ceruloplasmin as a marker of increased risk for coronary artery disease., This risk is attributed to the role of ceruloplasmin as an inflammatory marker such as CRP. Increased ceruloplasmin levels may be associated with decreased levels of nitric oxide (NO) production which subsequently causes vascular dysfunction. Ceruloplasmin was found to be associated with incident HF, death, and cardiovascular disease in a cohort study which included 9,240 subjects followed up for 10.5 years.
Normal aortic stiffness in patients with WD may be a consequence of different mechanisms. Decreased levels of ceruloplasmin in WD may be related to decreased oxidative stress, inflammation, decreased levels of oxidized LDL, and increased levels of NO. Nevertheless, decreased levels of ceruloplasmin may be a protective factor against atherosclerosis in WD. On the other hand, chelators such as d-penicillamine and zinc have an antioxidative effect which may be protective. Long-term use of penicillamine may alter aortic ultrastructure and extracellular matrix. Hyperelastic skin change was described after long-term treatment with penicillamine in very early reports. Pasquali Ronchetti et al. showed increased elastin fiber production in the extracelluler matrix of the chicken aorta after penicillamine treatment. Preserved aortic stiffness may be a result of penicillamine treatment. Another possible important factor might be a zinc supplement. Several studies demonstrated the anti-atherosclerotic effect of zinc supplementation in rats. Although very early reports raised suspicion of an increased atherosclerotic process in WD, our findings did not support this observation.
The small number of patients is the major limitation. WD is early diagnosed and treated in our patient group. Aortic stiffness measurements at the time of diagnosis would clarify the effect of treatment which is unavailable in our study. Patients with WD usually have accompanying anemia related to hemolytic anemia; hovewer, anemia is chronic and compensated.
| Conclusion|| |
Aortic stiffness was similar between patients with WD and healthy controls in this study.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Cocoş R, Şendroiu A, Schipor S, Bohîlţea LC, Şendroiu I, Raicu F. Genotype-phenotype correlations in a mountain population community with high prevalence of Wilson's disease: Genetic and clinical homogeneity. PLoS One 2014;9:e102619.
Azevedo EM, Scaff M, Barbosa ER, Neto AE, Canelas HM. Heart involvement in hepatolenticular degeneration. Acta Neurol Scand 1978;58:296-303.
Kaduk B, Metze K, Schmidt PF, Brandt G. Secondary athrocytotic cardiomyopathy – Heart damage due to Wilson's disease. Virchows Arch A Pathol Anat Histol 1980;387:67-80.
Factor SM, Cho S, Sternlieb I, Goldfischer S. The cardiomyopathy of Wilson's disease. Myocardial alterations in nine cases. Virchows Arch A Pathol Anat Histol 1982;397:301-11.
Bagheri B, Akbari N, Tabiban S, Habibi V, Mokhberi V. Serum level of copper in patients with coronary artery disease. Niger Med J 2015;56:39-42.
] [Full text]
Islamoglu Y, Evliyaoglu O, Tekbas E, Cil H, Elbey MA, Atilgan Z, et al.
The relationship between serum levels of Zn and Cu and severity of coronary atherosclerosis. Biol Trace Elem Res 2011;144:436-44.
Grammer TB, Kleber ME, Silbernagel G, Pilz S, Scharnagl H, Lerchbaum E, et al.
Copper, ceruloplasmin, and longterm cardiovascular and total mortality (the Ludwigshafen Riskand Cardiovascular Health Study). Free Radic Res 2014;48:706-15.
Vlachopoulos C, Aznaouridis K, Stefanadis C. Prediction of cardiovascular events and all-cause mortality with arterial stiffness: A systematic review and meta-analysis. J Am Coll Cardiol 2010;55:1318-27.
Williams B, Mancia G, Spiering W, Agabiti RE, Azizi M, Burnier M, et al
. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur Heart J 2018;39:3021-104. doi: 10.1093/eurheartj/ehy339.
Ferenci P, Caca K, Loudianos G, Mieli-Vergani G, Tanner S, Sternlieb I. Diagnosis and phenotypic classification of Wilson disease. Liver Int 2003;23:139-42.
Hayashi H, Tatsumi Y, Yahata S, Hayashi H, Momose K, Isaji R. Acute hepatic phenotype of Wilson disease: Clinical features of acute episodes and chronic lesions remaining in survivors. J Clin Transl Hepatol 2015;3:239-45.
Ozturk S, Gurbuz AS, Efe SC, Iliaz R, Banzragch M, Demir K. QTc ınterval is prolonged in Wilson's disease with neurologic ınvolvement. Acta Clin Belg 2018;73:328-32.
Grandis DJ, Nah G, Whitman IR, Vittinghoff E, Dewland TA, Olgin JE, et al.
Wilson's disease and cardiac myopathy. Am J Cardiol 2017;120:2056-60.
Gassanov N, Caglayan E, Semmo N, Massenkeil G, Er F. Cirrhotic cardiomyopathy: Acardiologist's perspective. World J Gastroenterol 2014;20:15492-8.
Kazankov K, Munk K, Øvrehus KA, Jensen JM, Siggaard CB, Grønbaek H, et al.
High burden of coronary atherosclerosis in patients with cirrhosis. Eur J Clin Invest 2017;47:565-73.
Mukhopadhyay CK, Fox PL. Ceruloplasmin copper induces oxidant damage by a redox process utilizing cell-derived superoxide as reductant. Biochemistry 1998;37:14222-9.
Förstermann U, Xia N, Li H. Roles of vascular oxidative stress and nitric oxide in the pathogenesis of atherosclerosis. Circ Res 2017;120:713-35.
Völker W, Dorszewski A, Unruh V, Robenek H, Breithardt G, Buddecke E. Copper-induced inflammatory reactions of rat carotid arteries mimic restenosis/arteriosclerosis-like neointima formation. Atherosclerosis 1997;130:29-36.
Subrahmanyam G, Pathapati RM, Ramalingam K, Indira SA, Kantha K, Soren B. Arterial stiffness and trace elements in apparently healthy population – A cross-sectional study. J Clin Diagn Res 2016;10:LC12-5.
Fox PL, Mazumder B, Ehrenwald E, Mukhopadhyay CK. Ceruloplasmin and cardiovascular disease. Free Radic Biol Med 2000;28:1735-44.
Lee MJ, Jung CH, Hwang JY, Shin MS, Yu JH, Lee WJ, et al.
Association between serum ceruloplasmin levels and arterial stiffness in Korean men with type 2 diabetes mellitus. Diabetes Technol Ther 2012;14:1091-7.
Tang WH, Wu Y, Hartiala J, Fan Y, Stewart AF, Roberts R, et al.
Clinical and genetic association of serum ceruloplasmin with cardiovascular risk. Arterioscler Thromb Vasc Biol 2012;32:516-22.
Göçmen AY, Sahin E, Semiz E, Gümuşlü S. Is elevated serum ceruloplasmin level associated with increased risk of coronary artery disease? Can J Cardiol 2008;24:209-12.
Singh TK. Serum ceruloplasmin in acute myocardial infarction. Acta Cardiol 1992;47:321-9.
Shiva S, Wang X, Ringwood LA, Xu X, Yuditskaya S, Annavajjhala V, et al.
Ceruloplasmin is a NO oxidase and nitrite synthase that determines endocrine NO homeostasis. Nat Chem Biol 2006;2:486-93.
Dadu RT, Dodge R, Nambi V, Virani SS, Hoogeveen RC, Smith NL, et al.
Ceruloplasmin and heart failure in the atherosclerosis risk in communities (ARIC) study. Circ Heart Fail 2013;6:936-43.
Gromadzka G, Karpińska A, Przybyłkowski A, Litwin T, Wierzchowska-Ciok A, Dzieżyc K, et al.
Treatment with D-penicillamine or zinc sulphate affects copper metabolism and improves but not normalizes antioxidant capacity parameters in Wilson disease. Biometals 2014;27:207-15.
Thomas RH, Light N, Stephens AD, Avery NC, Kirby JD. Pseudoxanthoma elasticum-like skin changes induced by penicillamine. J Roy Soc Med 1984;77:794-8.
Pasquali Ronchetti I, Fornieri C, Baccarani Contri M, Quaglino D Jr, Caselgrandi E. Effect of DL-penicillamine on the aorta of growing chickens. Ultrastructural and biochemical studies. Am J Pathol 1986;124:436-47.
Jenner A, Ren M, Rajendran R, Ning P, Huat BT, Watt F, et al.
Zinc supplementation inhibits lipid peroxidation and the development of atherosclerosis in rabbits fed a high cholesterol diet. Free Radic Biol Med 2007;42:559-66.
[Figure 1], [Figure 2]
[Table 1], [Table 2]