Substantial prevalence of subclinical cardiovascular diseases in patients with hemophilia A evaluated by advanced electrocardiography
Introduction
Hemophilia A (HA) is an inherited bleeding disorder caused by the deficiency of coagulation factor VIII (FVIII) [1]. Based on residual FVIII levels, patients with HA (PWHA) are classified as having severe (<1%), moderate (1–5%) or mild (5–40%) HA. Most patients with severe HA may require regular prophylaxis with coagulation FVIII concentrate, while the rest are treated on-demand. Improved healthcare and early initiation of prophylaxis have significantly increased the life expectancy of PWHA, from 30 years in the mid-1960s to almost normal lifespan [2]. According to the latest annual global survey of world federation of hemophilia, 19% and 31% of PWHA are over 45 years old in Americas and in Europe, respectively [3]. Since the risk of developing cardiovascular disease (CVD) increases with age [4], older PWHA are also considered to be at risk for CVD events.
Several cohort studies have shown that PWHA have lower mortality from CVD than the general population [2,5,6]. This observation cannot be explained by a difference in prevalence of CVD risk factors and atherosclerosis. For example, the prevalence of hypertension in PWHA has been reported to be either similar [7], or even higher than the general population [8,9]. Furthermore, PWHA are not protected from developing atherosclerosis compared to a matched control group [10,11]. It is suggested that due to decreased FVIII, PWHA experience less atherosclerotic plaque rupture, or their plaque ruptures are “silent” and do not lead to arterial occlusion [12].
Over the past two decades, several advanced electrocardiography (A-ECG) measures, including those from derived vectorcardiography [13] and waveform complexity [14], have been used to detect cardiac disease with greater sensitivity using the standard resting 12‑lead ECG. Abnormal A-ECG results have been found in patients with coronary artery disease or coronary microvascular disease (CAD/CMVD), various cardiomyopathies, left ventricular hypertrophy (LVH), or left ventricular systolic dysfunction (LVSD) [[15], [16], [17]]. A-ECG results can also be statistically integrated to maximize diagnostic/prognostic accuracy for particular disease conditions, with notably higher accuracy than conventional ECG [[15], [16], [17], [18], [19], [20]]. Another advantage of A-ECG is that it can be performed rapidly and inexpensively in clinical practice, including in patients unable to participate in cardiac exercise or stress testing [15].
The present study aimed to determine whether PWHA (≥40 years) are protected from CVD compared to age-matched controls, as determined by A-ECG. The secondary objective was to use A-ECG to compare the A-ECG results between severe versus non-severe (moderate and mild) PWHA. To our knowledge, this study is the first to use A-ECG to investigate subclinical cardiac disease in PWHA.
Section snippets
Study design
The study was performed retrospectively as a clinical audit of a cohort of PWHA followed up at the Coagulation Unit, Department of Hematology, Karolinska University Hospital from 2005 to 2018. The study was approved by the Regional Ethical Review Board in Stockholm, and was conducted in accordance with the Declaration of Helsinki.
Patient inclusion criteria: 1) male patients diagnosed with HA; 2) ≥40 years old at the time of inclusion, since they are more likely to develop CVD than younger
Cardiovascular risk factors
Data on CVD risk factors were collected from historical medical documentation of all study participants. In both the PWHA and control groups, hypertension, diabetes and dyslipidaemia were defined per physician annotations, and obesity as body mass index (BMI) ≥30 kg/m2. Family history of CVD and smoking were not reliably recorded for all the participants, and were therefore not included as variables in the study. Since only one measurement of blood pressure (BP) was obtained for control
Advanced ECG acquisition and analysis
Digital 10-second resting 12‑lead ECGs were extracted from the local ECG storage system (MUSE® Cardiology Information System, Version 9.0 SP6, GE Healthcare, Chicago, IL, USA) and exported into de-identified .xml files. The .xml files were analysed using dedicated semi-automatic A-ECG software [15]. If a patient had multiple ECG files in the hospital system, the latest was analysed.
Measures of A-ECG included conventional ECG intervals, axes and voltages; multiple vectorcardiographic measures
Results
Initially, medical records of 190 PWHA (≥40 years) were reviewed, and 44 were found to have electronic ECG files and were thusly eligible for inclusion in the study (Fig. 1). Eleven of the 44 PWHA were then excluded, due to previous myocardial infarction (n = 5), angina (n = 2), transient ischemic attack (n = 2), retinal embolism and carotid stenosis (n = 1) or heart failure (n = 1), and another 4 due to paced rhythm (n = 2), atrial fibrillation with wide QRS complex (n = 1) and noisy ECG
Characteristics and CVD risk factors of the cohorts
Twenty-nine PWHA (median [interquartile range] 57 [47–70] years, all male) and 29 age-matched male controls (59 [48–68] years) were included in the study. Nine (31%) PWHA had severe HA, while 20 (69%) had non-severe HA, including 16 (55%) with mild HA and 4 (14%) with moderate HA. Nine (31%) PWHA were on prophylaxis, including 7 with severe and 2 with non-severe HA. Twelve (41%) patients had hepatitis C virus (HCV) infection, and 7 of them had anti-virus therapy; another 2 (7%) patients had
Risk of cardiac diseases predicted by A-ECG scores
The probability of having cardiac disease in general by A-ECG was higher in PWHA than in controls (84.6 [32.5–99.5] vs 0.6 [0.2–8.2] %, p < .001) (Fig. 2). Although patients with severe HA had a numerically lower probability for disease than those with non-severe HA, the difference was not statistically significant (70.8 [6.3–99.8] vs 85.3 [36.7–99.2] %, p = .46). While the probability for cardiac disease never exceeded 50% in any control, it did in 66% (19/29) of PWHA. Among the nineteen PWHA,
Discussion
The results from this study suggest that PWHA are not protected from developing CVD. Specifically, PWHA in this study had more subclinical cardiac disease by A-ECG than age-matched male controls, including higher likelihoods of heart disease in general, CAD/CMVD, and LVSD, as well as a higher prevalence of LVER.
The development of CVD among PWHA is known to be associated with hypertension, dyslipidemia and other traditional CVD risk factors [25]. Several studies have also shown that CVD risk
Conclusions
Overall results from this study suggest that PWHA are not protected from developing subclinical CVD. PWHA showed higher probability of developing LVSD, CAD/CMVD and LVH/LVER than age-matched controls as evaluated by A-ECG. These results indicate that it is important to monitor the risk of developing CVD in PWHA older than 40 years, especially considering that life expectancy in PWHA now approaches that of the non-HA population. In addition, patients with severe HA in this study tended to have
Funding
This research was supported grants from Svenska Sällskapet för Trombos och Hemostas (SSTH), and Stiftelsen för Koagulationsforskning vid Karolinska Institutet (grant number: stiftelse245).
CRediT authorship contribution statement
Yanan Zong: Formal analysis, Writing - original draft. Maren Maanja: Methodology, Investigation. Roza Chaireti: Investigation, Resources, Writing - review & editing. Todd T. Schlegel: Methodology, Writing - review & editing. Martin Ugander: Conceptualization, Writing - review & editing. Jovan P. Antovic: Conceptualization, Writing - review & editing, Supervision, Project administration.
Declaration of competing interest
TTS is a principal of Nicollier-Schlegel SARL (Switzerland), a company that performs ECG research consultancy with the software used in the present study. The other authors declare there is no conflict of interest with the contents of this article.
Acknowledgements
Thanks to Ann-Michele Francoeur for editing the first draft of the manuscript.
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