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Year : 2019  |  Volume : 22  |  Issue : 8  |  Page : 1120-1125

Aortic stiffness in patients with wilson's disease

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 Acceptance12-Apr-2019
Date of Web Publication14-Aug-2019

Correspondence Address:
Dr. A S Gurbuz
Department of Cardiology, Necmettin Erbakan University, Meram Faculty of Medicine, Meram, Konya - 42080
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/njcp.njcp_578_18

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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

How to cite this URL:
Gurbuz A S, Ozturk S, Efe S C, Demir K. Aortic stiffness in patients with wilson's disease. Niger J Clin Pract [serial online] 2019 [cited 2022 Nov 30];22:1120-5. Available from:

   Introduction Top

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.[1] 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.[2],[3] Latter, a larger postmortem study not only confirmed the myocardial involvement but also described a patient with premature atherosclerosis of left main coronary artery.[4]

Several studies showed an association between serum copper levels and atherosclerosis.[5],[6] 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.[7]

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.[8] 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 Top

Study population

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.

Echocardiographic examination

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].
Figure 1: Aortic pulse wave velocity calculated by SphygmoCor device

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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

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Statistical analysis

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 Top

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 1: Baseline clinical and biochemical characteristics of subjects

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Table 2: Medication, echocardiographic, and aortic stiffness parameters of subjects

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   Discussion Top

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.[9] 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.[10] 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.[11] 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.[12] 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.[13] 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.[14] Additionally, some studies reported possible association between cirrhosis and atherosclerosis, which may cause greater aortic stiffness in cirrhotic patients.[15] 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.[16] On the other hand, several studies showed an association between oxidative stress and atherosclerosis.[17] Copper caused vascular inflammation and neointima formation in rat carotid arteries.[18] A cross-sectional study found a relationship between serum copper level and increased aortic stiffness in 737 apparently healthy subjects.[19] Moreover, ceruloplasmin may be a source of redox active copper which may consequently cause oxidation of low-density lipoprotein (LDL) particles.[20] Lee MJ et al. showed that increased ceruloplasmin was independently related to increased aortic stiffness in men with type 2 diabetes.[21] Several studies proposed ceruloplasmin as a marker of increased risk for coronary artery disease.[22],[23] This risk is attributed to the role of ceruloplasmin as an inflammatory marker such as CRP.[24] Increased ceruloplasmin levels may be associated with decreased levels of nitric oxide (NO) production which subsequently causes vascular dysfunction.[25] 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.[26]

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.[27] 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.[28] Pasquali Ronchetti et al. showed increased elastin fiber production in the extracelluler matrix of the chicken aorta after penicillamine treatment.[29] 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.[30] 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 Top

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 Top

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  [Table 1], [Table 2]


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