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Challenges and Opportunities in Cardiovascular Health Informatics

Yuan-Ting Zhang , Fellow, IEEE, Ya-Li Zheng, Wan-Hua Lin, He-Ye Zhang, and Xiao-Lin Zhou
AbstractCardiovascular health informatics is a rapidly evolving interdisciplinary eld concerning the processing, integration/ interpretation, storage, transmission, acquisition, and retrieval of information from cardiovascular systems for the early detection, early prediction, early prevention, early diagnosis, and early treatment of cardiovascular diseases (CVDs). Based on the rst authors presentation at the rst IEEE Life Sciences Grand Challenges Conference, held on October 45, 2012, at the National Academy of Sciences, Washington, DC, USA, this paper, focusing on coronary arteriosclerotic disease, will discuss three signicant challenges of cardiovascular health informatics, including: 1) to invent unobtrusive and wearable multiparameter sensors with higher sensitivity for the real-time monitoring of physiological states; 2) to develop fast multimodal imaging technologies with higher resolution for the quantication and better understanding of structure, function, metabolism of cardiovascular systems at the different levels; and 3) to develop novel multiscale information fusion models and strategies with higher accuracy for the personalized predication of the CVDs. At the end of this paper, a summary is given to suggest open discussions on these three and more challenges that face the scientic community in this eld in the future. Index TermsBody sensor networks, CVD, fast imaging, health informatics, information fusion, unobtrusive sensing, wearable devices.

I. INTRODUCTION

ARDIOVASCULAR DISEASE (CVD) is still the leading cause of death over the world. As reported by the World Health Organization, around 17.3 million people died from CVD

Manuscript received December 16, 2012; revised January 28, 2013 and January 29, 2013; accepted January 29, 2013. Date of publication February 1, 2013; date of current version March 7, 2013. This work was supported in part by the National Basic Research Program 973 (2010CB732606), the Guangdong Innovation Research Team Fund for Low-Cost Healthcare Technologies in China, the External Cooperation Program of the Chinese Academy of Sciences (GJHZ1212), the Key Lab for Health Informatics of Chinese Academy of Sciences, and the National Natural Science Foundation of China (81101120). Y.-L. Zheng, W.-H. Lin, and H.-Y. Zhang contributed equally to this work. Asterisk indicates corresponding author. Y.-T. Zhang is with the Joint Research Centre for Biomedical Engineering, Department of Electronic Engineering, The Chinese University of Hong Kong, Hong Kong, and also with the Key Laboratory for Health Informatics of the Chinese Academy of Sciences (HICAS) at SIAT, Shenzhen 518055, China (email: ytzhang@ee.cuhk.edu.hk). Y.-L. Zheng is with the Joint Research Centre for Biomedical Engineering, Department of Electronic Engineering, The Chinese University of Hong Kong, Hong Kong (e-mail: ylzheng@ee.cuhk.edu.hk). W.-H. Lin, H.-Y. Zhang, and X.-L. Zhou are with the SIAT-Institute of Biomedical and Health Engineering, Chinese Academy of Sciences, and also with the Key Laboratory for Health Informatics of the Chinese Academy of Sciences (HICAS) at SIAT, Shenzhen 518055, China (e-mail: wh.lin@siat.ac.cn; heye.zhang@gmail.com; xl.zhou@siat.ac.cn). Color versions of one or more of the gures in this paper are available online at http://ieeexplore.ieee.org. Digital Object Identier 10.1109/TBME.2013.2244892

in 2008, accounting for 30% of global deaths [1]. In the next decades, because of the impacts of hypertension, obesity, and diabetes, and increasing number of the elderly, the number of CVD deaths is estimated to be up to 23.6 million by 2030 [1]. Among all the deaths caused by CVD, about two-thirds of them happen in out-of-hospital settings [2]. Furthermore, the CVD will increase the economic burden largely upon our society. As the most important chronic disease, CVD can be caused by long-term cumulative effects of behavioral risk factors of tobacco use, unhealthy diet, or insufcient physical activity, in most of cases together with metabolic and physiological risk factors of high blood pressure (BP), raised serum cholesterol, and impaired glucose metabolism [3]. Moreover, because of the lack of effective monitoring of health status and accurate predictive tools, a large number of people die from acute cardiovascular events without prior symptoms [4]. Thus, in recent decades, the consensus on effective prevention and control of CVDs is to monitor and reduce the risk factors, and improve the management and healthcare through early detection and timely treatment at an early stage before obvious symptoms develop [5]. Advancing health informatics, determined as one of the 14 grand challenges for engineering in the 21st century by the U.S. National Academy of Engineering [6], is crucial for realizing the preventive medicine and implementing other p-Health technologies including Predictive, Personalized, Precise, Pervasive, Participatory, Preemptive Healthcare [7]. From a biomedical engineering perspective, the development of cardiovascular health informatics requires the collection, processing, and analysis of health information of the cardiovascular system, in order to understand the mechanism of CVD and prevent the development of CVD in its early stage. This development eventually will benet early detection, early prediction, early diagnosis, and early treatment of CVD [7]. To accelerate the development of cardiovascular health informatics and engineering, a series of international funding projects have been announced. In 1990s, the Cardiome Project, a part of Physiome Project, developed an integrated model of normal working heart upon an international efforts [8]. In 2004, the Heart Physiome Project funded by the Wellcome Trust developed a multiscale cardiac functional modeling platform between New Zealand and U.K. One wellknown output of this project is the demonstration of the mechanisms that underlie cardiac arrhythmia and brillation [9]. In 2008, the European Commission provided EUR13.90 million to support the euHeart Project (FP7-2008-IST-224495) for developing patient-specic cardiovascular modeling framework for integrated cardiac care [10]. In the same year, the HeartCycle project was supported with a budget of around EUR 20.7 million, of which EUR 14.1 million was funded by the European

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Union as part of the EU 7th Framework Program, for improving care of heart patients through the development of innovative telemonitoring solutions and closed-loop patient management systems [11]. In 2009, the Chinese National Basic Research 973 Program supported a joint research project (2010CB732606) with a budget of RMB 28 million for developing multimodal high-resolution imaging technologies, unobtrusive multiparameter devices, and multiscale computation models for the personalized screening and objective risk assessment of vulnerable patients with blood plaque. Despite a number of major grants and signicant efforts devoted to developing screening and diagnostic methods that can be used for the prediction of CVDs, identifying victims before acute cardiovascular events occur remains a grand challenge. Therefore, there is still a strong need to advance cardiovascular health informatics with the emphasis on the development of screening tools with higher sensitivity and risk assessment methods with higher specicity for accurately and early identifying people at CVD risk. Previous studies reported by 58 medical experts have shown that vulnerable patients were characterized as having vulnerable plaques (prone to thrombotic complications and rapid progression), vulnerable blood (prone to thrombosis), and vulnerable myocardium (prone to fatal arrhythmia), placing those people at high risk of developing acute cardiovascular events [4]. Therefore, cardiovascular information acquisition can focus on developing theories, technologies, and systems that are essential for addressing vulnerable patients problems such as screening vulnerable plaques, vulnerable blood, and vulnerable myocardium using the solutions of biomarker detection and biomedical imaging [4], [12], [13]. In addition, the Ohasama study suggested that daytime systolic ambulatory BP variability and heart rate (HR) variability should be considered as independent risk factors for CVD mortality in the general population [14]. The Dublin study showed that the nighttime BP can be more effective in predicting CVD mortality [15]. Those important clinical ndings indicate a strong need for unobtrusive devices for the continuous and real-time monitoring of risk factors for CVD mortality prediction. It has been shown recently that computational models integrating multiscale health information can provide another perspective for a quantitative assessment of the physiological and pathological activities of organism from simulation environment [8]. However, the lack of patient-specic features is an obstacle for these models to be applied into daily clinical practices. Even a personalized model can be constructed; the real challenge in modeling is to develop ones that can be inverted to allow a particular set of observations to predict the cardiac mechanisms that are producing the observed signals. A notable example is Y. Rudys work to reconstruct the distribution of action potential or the activation pattern over the surface of epicardium using an individuals body surface of electrocardiogram (ECG) and a Poisson model constraint [16]. Another notable example of the inverse problem is B. Hes effort to develop a model-based framework to reconstruct the electrophysiological activities of the whole heart from noninvasive body surface ECG

measurements [17][19]. The potential of this model-based inverse framework has been demonstrated by others [20], [21]. There are many roadblocks to progress. In this paper, we propose and discuss following three core topics as the grand challenges of cardiovascular health informatics for the coming decades to achieve the ultimate goal of early detection, early prediction, early diagnosis, and early treatment of acute CVD. 1) To invent unobtrusive sensors for the real-time and continuous collection of physiological information, from which critical risk index can possibly be extracted for the prediction of the rupture of vulnerable plaques and the occurrence of acute CVD events. 2) To develop fast high-resolution imaging technologies for the objective evaluation of atherosclerotic risk, vulnerable plaque, and vulnerable myocardium. 3) To solve the inverse cardiovascular problem and develop information fusion theories and technologies over the computational modeling platform for integrating health information across multiscales, from molecules, cells, tissues, organs, to systems levels, for patient-specic quantitative assessment of CVD. II. TO INVENT UNOBTRUSIVE SENSORS FOR THE REAL-TIME AND CONTINUOUS ACQUISITION OF CARDIOVASCULAR HEALTH INFORMATION Unobtrusive monitoring devices for CVD applications are designed to acquire physiological and behavioral signals and variables without interrupting the subjects daily life or even without consciousness, such as ECG, photoplethysmogram (PPG), respiratory rate, HR, temperature, blood oxygen saturation, BP, posture and kinematic activity, etc. Unobtrusive monitoring devices can be implemented in two ways: 1) by embedding wearable sensors into clothing [22] or accessories, such as earring [23], ring [24], glove [25], and 2) by embedding ambient sensors in everyday objects, such as furniture, appliance, construction [26][28], etc. Unobtrusive sensing can also be classied into two types according to the source of the signals, i.e., passive and active. Some of passive sensing methods can be realized for unobtrusive detection of signals from the human body, such as the capacitive-coupling-based ECG measurements. Unobtrusive active sensing, on the other hand, emits energy to human body and then detects the reected or backscattered radiation from it, such as the radio or radar approach to detect HR remotely or remote infrared temperature measurements. Connected through the wireless communication technologies, the acquired physiological health information from unobtrusive devices can be transmitted to a remote control center. In this way, the patients CVD state can be remotely monitored in outof-hospital conditions in real time. Not only can it greatly reduce the medical cost caused by frequent visits to hospital, but also allow taking preemptive actions in response to the acute CVD events. More importantly, some out-of-hospital measurements may be more valuable for the clinical diagnosis and treatment of CVDs. It has been gradually recognized that clinical BP may fail to provide adequate information of the true BP and might give misleading information in clinical diagnosis, such as white-coat

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hypertension. A joint scientic statement recommended that home BP monitoring should become a routine component of BP measurement in patients with known or suspected hypertension [29]. Moreover, other clinical studies have demonstrated that 24-h BP measurement can provide more valuable and independent risk factors for the prediction of CVD mortality. The Dublin study showed that the relative hazard ratios (RHR) associated with 10 mmHg increase in systolic BP for CVD mortality were 1.02 (95% CI, 0.99 to 1.05), 1.12 (1.06 to 1.19), 1.21 (1.13 to 1.28), 1.19 (1.13 to 1.27) for ofce BP, daytime, nighttime, and 24-h ambulatory BP, respectively [15]. The Ohasama study showed that daytime systolic ambulatory BP variability has a signicant linear relation with RHR for CVD mortality [14]. These results indicated that ambulatory BP and its variability, especially nighttime BP, are superior risk predictors of CVD events over clinical BP [15]. Therefore, it holds great signicance to develop unobtrusive devices for real-time and continuous monitoring physiological states of CVD patients overnight or for a whole day. Researchers have devoted great efforts in recent years to promote the application of unobtrusive monitoring devices in CVD healthcare. For ECG measurement, instead of adhering wet gel electrodes directly to the surface of body, dry/noncontact electrodes based on capacitive coupling and embedded in furniture provide an effective solution for unobtrusive sensing of ECG [30][32]. A simple and noncontact pulse sensing technique proposed by Poh et al. can automatically calculate the HR from digital color video recordings of the human face region, from which the blood volume pulse can be extracted by the independent component analysis method [33]. K. Humphreys et al. also built a noncontact PPG system with dual wavelength via camera-based instrument towards remotely measuring the blood oxygen saturation [34]. The pulse-wave-velocity (PWV)-based BP estimation technique provides a very promising method for continuous and cuff-less BP measurement. Pulse transit time (PTT), dened as the time it takes for the pulse to travel from the heart to the peripheral, can be simply measured from ECG and PPG signals. Extensive studies have been conducted to justify the potential of PTT as a surrogate of BP [35][41]. The results of an experimental test on 85 subjects showed that the estimated systolic and diastolic BP by PTT differed from the reference BP by 0.6 9.8 mmHg and 0.9 5.6 mmHg, respectively, which is comparable to the Association for the Advancement of Medical Instrumentation (AAMI) requirement, i.e., 5 8 mmHg for systolic and diastolic BP estimation, as shown in Fig. 1(a) [36]. Some efforts have been devoted to establishing new standards for the evaluation of the accuracy of cuff-less BP measurement devices [42]. This kind of cuff-less BP estimation method can be easily implemented into furniture such as a normal chair [43], and a sleeping cushion [32] for the continuous and unobtrusive monitoring of HR, PTT, BP, and other physiological parameters, as shown in Fig. 1(b). Another concern in the development of unobtrusive devices is the comfort of use and user-friendly design. For wearable implementation, technologies of smart textiles have undergone extensive development in recent years, aiming to provide an effective and practical solution for seamlessly integration of

Fig. 1. (a) Mean and standard deviation of the difference in BP by different methods compared with AAMI standard [36]. (b) Prototypes of unobtrusive devices: a smart health chair [43] and a sleeping cushion for unobtrusive HR and BP measurement [32].

all wearable sensors into a single garment, which is the essential part of our lives, offering promise for future wearable devices [44]. Moreover, the emerging area of exible electronics provides a brand new way to design the wearable devices [45]. The critical features of these exible electronics including the exible structure, light weights, and biocompatibility will push wearable devices a step further toward completely unobtrusive monitoring. Though signicant progresses have been made in the past few years, there are still several great technical challenges to be overcome to implement unobtrusive monitoring in real life, some of which are proposed below to call for more emphasis in the future work: 1) To develop real-time, unobtrusive, and continuous methods for measuring multiphysiological parameters and monitoring human behaviors including physical activities. 2) To invent model-based approaches for the unobtrusive and cuff-less estimation of BP including central BP. Though PTT-based BP estimation is very promising for cuff-less BP measurements, some confounding factors limited the accuracy of this technique, such as preejection period [39], [46][48] and vascular tone [46], [49]. Quantitative models taking into account these effects are needed to gain deeper insight into the PTT-BP or PWV-BP relationship to improve the accuracy of this technique. 3) To develop effective motion artifacts (MA) reduction or removal methods. Though numerous solutions have been proposed to address this problem of MA, such as designing motion-resistant sensing units together with advanced signal processing algorithms like adaptive noise cancellation methods [23], and estimating features through multisensor fusion based on signal quality assessment and MA

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identication [50], it is still a major obstacle to be overcome for achieving unobtrusive monitoring in real life. 4) To design the wearable devices of MINDS (i.e., the devices with the features of Miniaturization, Intelligence, Networking, Digitizing and Standardization (MINDS) [51] for the dynamic measurements of physiological and physical signals). Miniaturization is required to make the wearable devices being more comfortably and conveniently worn by the patients without affecting their daily activities. Intelligent feature allows a user to operate wearable devices easily and ideally can support onset decision-making or warning if needed. Networking wearable or implantable devices [52] can form a body sensor/area network enabling m-Health applications [30], [53], [54]. Digitization of all the analogue signals is a must for information acquisition, transmission, and processing. Standardization will ensure the objective evaluation of performance of these devices as well as for their industrialization [42]. III. TO DEVELOP HIGH-RESOLUTION IMAGING FOR DETERMINING ATHEROSCLEROTIC RISK AND SCREENING VULNERABLE PLAQUE AND VULNERABLE MYOCARDIUM Atherosclerosis is the main cause of acute CVD [55]. The development of atherosclerosis may lead to unstable atherosclerotic plaque or vulnerable plaque which is characterized as active inammation, a thin brous cap with a large lipid core, erosion or ssure of the plaque surface, intraplaque hemorrhage, and supercial calcied nodules [55], [56]. Vulnerable plaque could narrow blood vessels or even occlude the vessel, resulting in the block of blood ow to vital organs, such as the heart and the brain. If the treatment of atherosclerosis is delayed, subsequently the rupture of vulnerable plaque would cause acute coronary death or stroke [55]. In addition, other kinds of cardiac diseases, such as myocarditis, electrophysiological disorders, heart valvular disease, and other cardiomyopathies (hypertrophic, dilated, orrestrictive), are often related to vulnerable myocardium [4]. Therefore, the successful prevention of CVD depends on whether atherosclerotic risk, vulnerable myocardium, and vulnerable plaques, which have high likelihood of thrombotic complications and rapid progression, can be characterized as early as possible [13]. Both invasive and noninvasive imaging modalities have provided an insight into the structure and progression of asymptomatic atherosclerosis, vulnerable myocardium and plaque [12], [13]. Some invasive imaging modalities such as catheterization or mini-invasive tests such as optical coherence tomography and intravascular ultrasound (IVUS) have been used clinically for evaluating the vulnerability of plaque. Photoacoustic imaging technique opens a new area for intravascular imaging [57]. In comparison with IVUS, the photoacoustic imaging technique with high spatial resolution can provide more detailed information of plaques. Because of the convenience and cost-effectiveness, noninvasive imaging modalities are more frequently used for screening subclinical atherosclerosis, high-risk plaque, and myocardium

Fig. 2. Noninvasive imaging techniques for early identication of CVD. Reproduced from [13]. (a) Example of an image captured by ultrasonography. The arrow indicates plaque burden. (b) Example of an image captured by CT technology. The arrow shows calcication. (c) Example of an image captured by MRI. The arrow indicates lipid deposit. (d) Examples of images captured by PET, CT, and combined PET/CT. The visual target outlines the carotid artery.

vulnerability. Now many well-established risk factors are measured by standard clinical imaging modalities, such as carotid intima-media thickness and ankle brachial index captured by ultrasound (US) imaging, and the coronary artery calcium score calculated by computerized tomography (CT) imaging [58]. These risk factors have been proved to be highly associated with the occurrence of fatal events, and are widely used in the clinical guideline for the assessment of cardiovascular risk in asymptomatic adults [59]. Fig. 2 provides some examples of using noninvasive imaging techniques for identication of CVD [13]. Prominently, CT technology can assess plaque composition, level of calcication, and coronary stenosis [13]. Magnetic resonance imaging (MRI) can reliably detect and quantify carotid/aortic plaque components such as lipids, bro-cellular tissue, calcium, intraplaque hemorrhage [60], assess atherosclerotic burden, and potentially, plaque perfusion in noncoronary arteries [13]. Several promising approaches to improve the MRI resolution have been reported such as multichannel coil design [61], compressive sensing algorithms [62], partially separable functions [63], parallel imaging algorithm [64], graphic processing unit technology [65], and non-Fourier encoding methodology [66]. Molecular imaging built on platforms of MRI, positron emission tomography (PET), single-photon emission computed tomography (SPECT), CT, US, and combined PET-CT, such as [18 F] uorodeoxyglucose PET-CT [60] can help in detecting plaque inammation [13], [67]. Currently, single molecule detection has gained great attentions because of its potential in locating plaques through biomakers. The quantum-dot-based molecular imaging with ultrasensitivity has great potential for cardiovascular applications [68], [69]. Molecular beacon imaging technology can illuminate beacons of disease state without the need to reconstruct an image of the entire heart [70]. Table I presents the sensitivity and application status of using noninvasive imaging techniques for screening atherosclerotic plaque, which was collected by Kips et al. [12], etc. As can be seen from the Table, each of the current technologies has one

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TABLE I NONINVASIVE IMAGING FOR SCREENING ATHEROSCLEROTIC PLAQUE

or more limitations upon spatial/axial resolutions, penetration depth, and tissue characterizing capability, which will affect detection of vulnerable plaques in time [12]. Other limitations, such as the high investment of imaging machines (e.g., MRI, Multidetector CT), high expenditure on the tests using these devices, and potential risk derived by radiation exposure of CT, SPECT, PET, prevent current imaging modalities from being used for conventional examinations in daily clinical practices. In the end, because the movement of cardiac system, respiratory, swallow, blood ow, and casual body movement will cause blurred images, poor contrast ratio, and even failure of the examination, the duration of the 3-D volume imaging of the heart, especially for MRI, should be greatly reduced [71]. Therefore, improving both temporal and spatial resolution of biomedical imaging is crucially important for CVD applications. Higher resolution imaging will allow the early screening of vulnerable plaque and vulnerable myocardium, and early identication of atherosclerosis during clinical practices. Grand technical challenges in this area are to develop high-resolution imaging modalities with high sensitivity and high contrast that can be used for the objective evaluation of vulnerable plaque including its morphostructure and components, and for the detection of pathological markers. The challenges and opportunities in cardiovascular imaging include but not limited to the following topics: 1) To develop real-time and high spatial resolution imaging methods (especially for MRI) with the removal of the MA of dynamic organs for screening the vulnerable patients with plaque. 2) To develop molecular imaging technology with high sensitivity for detecting biomarkers of inammation activities and pathologies in atherosclerotic plaque, myocardium, etc. 3) To develop multimodal imaging modalities for identifying and quantifying plaque components (e.g., brous cap and lipid core) with high accuracy. IV. TO DEVELOP INFORMATION FUSION MODEL FOR EARLY PREDICTION OF CVD The increasing number of technologies, such as physiological monitoring, high-resolution imaging, biomarker detection, gene sequencing and so on, have provided a huge amount of information of the heart, spinning multiscales from gene, protein, cell, tissue, organ, to the system [7], [8]. Therefore, integrating

multiscale information of the cardiovascular system for understanding the CVD progress comprehensively and precisely and predicting the CVDs early is becoming one great challenge at present. Because of advances in computing power and the understanding of the cardiac system, the electrophysiological, biomechanical, and the hydrodynamic models of cardiovascular system have been able to simulate many kinds of physiological behaviors of the heart. Hence, the challenge of information fusion for early prediction of CVD should be met by developing model-based fusion frameworks or technologies to personalize multiphysics models using personal multiscale health information obtained by multiparameter sensing and multimodal imaging techniques [72]. In order to understand the cause of CVD, quite a large number of efforts have been spent on developing computational models for simulating the physiology and pathology of cardiovascular system, and applying these models for nding the causes of CVD. The capabilities of these models vary signicantly from simulating of the heart function, hemodynamics of arterial system, to the whole cardiovascular system including blood circulation [73], [74]; so is the complexity of these models, from simple zero-dimensional Windkessel model to complex multiscale, multiphysics models which incorporating from cells to systemic circulation [74]. One particularly great collaboration should be emphasized here is Cardiac Physiome Project. With an international contribution, this project has made a great progress in developing a multiphysics model, which has the coupling of metabolic, electrophysiological, and biomechanical process, for integrating the cardiac structure-function relations at multiscale across from cell, tissue, to organ levels as shown in Fig. 3 [8]. In this project, the biomodel-based coupling approaches have been extensively used for combining cardiac continuum tissue mechanics with electrophysiology, ventricular blood ow, and coronary hemodynamics in a meaningful physiological sense [75]. Another similar multiscale framework is the Virtual Physiological Rat Project, which develops a multimodel platform with a coupling of metabolic and electrophysiological processes [76]. Furthermore, computational modeling of the human vascular system enables the simulation of the hemodynamics in arterial bifurcations and arterial stenosis, where the heart attack or stroke is prone to occur [77]. In these elds of research, computational models were applied to simulate two main processes (plaque rupture [78] and thrombus formation [79]) that lead to heart attack or stroke, in coronary and carotid arteries, respectively. The success in modeling of the cardiovascular

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Fig. 3.

Diagram of Cardiac Physiome Project. Reproduced from [8]. Fig. 5. Illustration of multiscale modeling of cardiovascular system [84].

Fig. 4.

Framework of the proposed prediction model [83].

system has greatly improved the understanding of clinical applications. For example, a multiscale model that includes mitral valve dynamics was used to understand ischemic mitral insufciency [74]. Another two models were used for evaluating the effect of cardiovascular system drugs [80] or planning of surgery [81]. Despite the great achievements in computational modeling of physiology and pathology of the cardiovascular system, the information fusion for personalizing the model of cardiovascular system, which eventually will benet for quantitative assessment of the risk of specic patient, is still a challenge. Since atherosclerotic plaque rupture with subsequent thrombosis accounts for most of fatal acute myocardial infarction and/or sudden coronary deaths [82], many strategies of information fusion have been developed for understanding or predicting this clinical event. Our group has proposed a personalized model for quantitative assessment of the risk of acute cardiovascular events based on vulnerable plaque rupturing mechanism [83]. The framework of this personalized prediction model is shown in Fig. 4. The model not only takes traditional risk factors, sensitive biomarkers, blood biochemistry, vascular morphology, plaque

information, and functionality image information as inputs of the prediction system, but also gathers physiological information continuously from unobtrusive devices and body sensor networks for near-term risk assessment of acute cardiovascular events. In another example, a multiscale computational modeling framework (see Fig. 5) of the entire cardiovascular system was established as one closed loop for studying the global hemodynamic inuences of aortic valvular and arterial located in various regions [84]. In order to understand the information collected by different means, the control theories have been introduced to our community as one powerful information fusion strategy [85][88]. Furthermore, this control-theory approach was also applied to detect the pathologies of cardiac electrophysiology through the reconstruction of cardiac action potential over myocardium [20], [89]. Though the potentials of information fusion strategies are gradually recognized, because of the modalities and the quantities of measurements of cardiovascular parameters are still increasing, the challenge of information fusion for early prediction of CVD becomes more difcult. Recently, a computing platform named OpenCMISS has been developed for solving the problem caused by the huge side of data to information fusion [90]. In this platform, simulation of cardiac system from cellular to organ level, and information fusion using imaging or biosignal data are integrated together over an efcient parallel computing system, which makes the process of big data and information fusion become feasible in near future. Furthermore, OpenCMISS is an open-source project, which means anyone can use it freely as the starting point to build his or her own fusion framework. This will greatly benet the defeat of challenge in information fusion. To overcome the difculties and achieve the goal, there is still much to be done. The challenges of information fusion for early prediction of CVD are outlined as follows: 1) To extract new risk factors at multiple scales from cardiovascular systems with both high sensitivity and specicity, and to integrate physiological information, biomarker information, and blood biochemistry with cardiovascular

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2)

3)

4)

5)

imaging information for screening vulnerable plaque and vulnerable patient. To include physiological mechanisms, especially wholecell function, subcellular process, metabolic and signal transduction pathways in the information fusion model for understanding the progress of a series of cardiovascular events, such as atherosclerotic plaque rupture, thrombus formation [8], [73], [91], etc. To rene the cardiovascular models at different scales incorporating metabolism and functions remains an ongoing challenge. The advances of continuous measurement of physiological parameters, dynamic biology imaging, high-resolution imaging, genomic and proteomic data, and cellular and tissue properties can provide a wealth information of cardiovascular system, which offers a signicant opportunity to rene the model with more features [75]. For instance, with the advances in diffusion tensor MRI for quantifying ber orientation [92], cardiac ber structure now can be well modeled and simulated. To design the boundary conditions based on biophysical and biochemical laws for coupling models with different dimensions/scales across common boundaries and for assimilating different information. Common boundaries based on models of biomechanics were introduced by Nordsletten et al. for coupling multiphysics inside one cardiac model [75]. Such couplings could be extended to other parts of the cardiovascular system, such as the interaction of inammatory cells and brous cap tissue, with vessel hemodynamics that regulate the formulation, progression, and rupture of plaque. To improve the efciency of computing algorithms. Highly efcient computing algorithms should be carefully designed for managing and processing the huge amounts of multimodal data with acceptable time cost. V. SUMMARY

applicable to other CVDs with appropriate modications, such as arrhythmia, cardiac myocarditis, heart valvular disease, and other cardiomyopathies. In summary, the ideal technologies for early identication of CVD should be cost-effective, relatively noninvasive, and widely reproducible, so that the technologies can be adopted for monitoring and screening of the asymptomatic population. After that, stepwise approaches should be designed to further stratify risk, provide reliable diagnosis, and offer avenues for convenient treatment or intervention. Though the main focus of this paper is to discuss the noninvasive or even unobtrusive techniques, it cannot be ignored that the popular mini-invasive imaging techniques, such as photoacoustic imaging, also show great potentials in early screening of CVD. Furthermore, the biochemical measurements from blood also can provide reliable CVD biomarkers, where the microuidic devices or bio-MEMS using emerging nanotechnology have been able to achieve high-sensitivity detection of the markers [93], and multiplexed detection of different markers simultaneously [94]. Meanwhile, it is noteworthy that the effectiveness of the novel cardiovascular risk markers developed by new technologies should be validated before it is adopted in standard clinical care according to the following procedures: primary proof of concept, prospective validation in independent individuals, proof of extra information when added to established risk markers, evaluation of effect on patient managements, and nally cost-effectiveness, which are dened by the American Heart Association [95]. At the end, we should point out that the prevention of CVD is easier than the cure of CVD. Most of CVD is preventable by adopting a healthy lifestyle, such as exercise, diet modication, and nonpharmacological means of BP regulation (reduced salt, etc.).

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The emerging technologies in cardiovascular health informatics, which mainly deals with the acquisition, processing, fusion, and interpretation of multiscale and multimodal cardiovascular health information, open new opportunities for better understanding the pathologies of CVDs, developing preferable personalized risk assessment tools to screen high-risk patients at early stage, motivating the patients identied at cardiovascular risk adhere to therapeutic lifestyle modication, and eventually achieving the goal of early detection, early predication, early diagnosis, and early treatment of CVDs. Health informatics, in general, can accelerate the paradigm shift from traditional medicine to the 6-Ps health care or p-Health, i.e., the participation of the whole nation for the prevention of illnesses or early prediction of diseases such that preemptive treatment can be delivered to realize pervasive and personalized healthcare [51]. In this paper, we have discussed three grand challenges related to sensing, imaging, and information fusion with the aims at promoting the fast development of reliable technologies for the early identication and prediction of acute CVD in the near future. The discussion of these three challenges may also be

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Ya-li Zheng received the B.E. degree in electronic science and technology from Beijing Jiaotong University, China, in 2007, and the M.S. degree in microelectronics and solid states electronics from Peking University, Beijing, China, in 2010. She is currently working toward the Ph.D. degree in electronic engineering at the Chinese University of Hong Kong, Hong Kong. Her current research interests include noninvasive blood pressure measurement, modeling of physiological systems, and wearable medical devices for p-health.

Wan-Hua Lin received the B.E. and M.E. degrees from Central South University, Changsha, China, in 2006 and 2009, respectively. She is currently working as an Assistant Professor at the Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, ShenZhen, China, and the Key Laboratory for Health Informatics of the Chinese Academy of Sciences (HICAS), Shenzhen.

Yuan-Ting Zhang received the undergraduate and Masters degree in telecommunication from the Department of Electronics, Shandong University, China, in 1976 and 1981, respectively, and the Ph.D. degree in electrical engineering from the University of New Brunswick, NB, Canada, in 1990. He is currently the Director of Joint Research Center for Biomedical Engineering and Professor of Department of Electronic Engineering at the Chinese University of Hong Kong (CUHK). He serves concurrently the Director of the Key Lab for Health Informatics of the Chinese Academy of Sciences (HICAS) at SIAT. He is the founding Director of the CAS-SIAT Institute of Biomedical and Health Engineering and the founding Head of the Division of Biomedical Engineering at CUHK. His current research interests include wearable medical devices, body sensor networks, physiological modeling, neural engineering, cardiovascular health informatics, and m-u-p-Heath technologies. Dr. Zhang holds the fellowships from the International Academy of Medical and Biological Engineering (IAMBE), the Institute of Electrical and Electronics Engineers (IEEE), and the American Institute of Medical and Biological Engineering (AIMBE) in recognition of his outstanding contributions to the development of wearable medical devices and mobile health technologies. He serves currently on IEEE-EMBS Technical Committee on Information Technology in Biomedicine, HK-ITC Projects Assessment Panel, IAMBE Fellow Membership Committee, and the Editor-in-Chief of IEEE JOURNAL OF BIOMEDICAL AND HEALTH INFORMATICS which was retitled from T-ITB in Jan. 2013. He received the IEEE-EMBS outstanding service award in 2006. His research work has won him and his students/teams numerous honors/awards including the best journal paper awards from the IEEE-EMBS, best conference paper awards, and the Grand Award in e-Health at the Asia-Pacic ICTAAC in Melbourne in 2009. He was elected to the AdCom of IEEE Engineering in Medicine and Biology Society (EMBS) in 1999 and became previously the Vice-President of the IEEE-EMBS in 2000. He served as the Technical Program Chair and the General Conference Chair of the 20th and 27th IEEE-EMBS Annual International Conferences in 1998 and 2005, respectively. He also served on the IEEE Medal on Innovations in Healthcare Technology Award Committee and IEEE Fellow Elevation Committee, and he was Editor-in-Chief of IEEE TRANSACTIONS ON INFORMATION TECHNOLOGY IN BIOMEDICINE (T-ITB).

Heye Zhang received the B.S. and M.E. degrees from Tsinghua University, Beijing, China, in 2001 and 2003, respectively, and the Ph.D. degree from Hong Kong University of Science and Technology, Hong Kong, in 2007. He is currently an Associate Professor at the Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences (CAS), ShenZhen, China. He is also with the Key Laboratory for Health Informatics of the Chinese Academy of Sciences (HICAS), China. His research interests include cardiac electrophysiology and cardiac image analysis.

Xiaolin Zhou received the Ph.D. degree in information systems from the University of Aizu, AizuWakamatsu, Fukushima, Japan, in 2011. He is now an Assistant Professor at the Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, ShenZhen, China. He has authored and co-authored over 20 journal and conference papers, and holds two patents. His research interests include biomedical signal processing, smart monitoring system, and relevant software development.