DDMOD-403; No of Pages 7

Vol. xxx, No. xx 2014

Drug Discovery Today: Disease Models

Editors-in-Chief
Jan Tornell AstraZeneca, Sweden
DRUG DISCOVERY Andrew McCulloch University of California, SanDiego, USA
TODAY
DISEASE Computational models of heart diseases
MODELS

Ischemic heart disease and coronary

flow
Ghassan S. Kassab1,2,3,*
1
Department of Biomedical Engineering, Indiana University Purdue University, Indianapolis, IN, USA
2
Department of Surgery, Indiana University Purdue University, Indianapolis, IN, USA
3
Department of Cellular and Integrative Physiology, Indiana University Purdue University, Indianapolis, IN, USA

Ischemic heart disease (IHD) is a major cause of mor-

bidity and mortality in the world. The use of mathe-
matical models allows the integration of the structural/
mechanical/biochemical determinants of coronary
flow for understanding coronary physiology/pathophys-
iology as well as to provide avenues for diagnosis and
therapy of IHD. This review provides an overview of
coronary flow models in the deep layers of the heart
that are vulnerable to ischemia and models for non-
invasive determination of ischemic severity.
Introduction
Ischemic heart disease (IHD) is one of the most important
health problems in Western Society and remains a major
cause of morbidity and mortality in the US and is very much
on the rise around the world. IHD is the failure of sufficient
coronary blood supply to match the metabolic demands of
the heart. Despite the clinical relevance of this problem, the
coronary circulation remains poorly understood because clin-
ical work has largely focused on coronary artery disease
(atherosclerosis and associated risk factors) rather than on
the integration of the coronary circulation. The latter requires
a physics/mathematical modeling-based approach that takes
into account subject-specific anatomy, material properties
and hemodynamic boundary conditions. In this review, we
will present an overview of the mathematical models that
provide an understanding of the mechanical mechanisms of
*Current address: California Medical Innovations Institute, 11107 Roselle St., San Diego, CA
92121, USA.
Section editors:
Natalia Trayanova Institute for Computational Medicine,
Johns Hopkins University, Baltimore, MD, USA
Nicolas Smith Biomedical Engineering Department,
Kings College, London, London, UK
subendocardial ischemia. We will also present an overview of
patient specific mathematical models that provide a non-
invasive determination of fractional flow reserve (FFR) for
diagnosis of functional severity of myocardial ischemia. An
integration of these two models may provide subendocardial
FFR which may be more sensitive than the global FFR cur-
rently used clinically.
Advancements in high-performance computers have made
it possible to attempt anatomically based computational (dis-
tributive) models where subject-specific anatomical details of
the coronary vascular system are considered. Mathematical
modeling of coronary circulation is an important tool because
experimental approaches are highly limited, particularly in the
circulation of the deeper layer of the heart, which is not
amenable to direct visualization. Computational models are
also important because there are numerous variables that
impact the coronary circulation that elude an intuitive under-
standing. The mathematics of the laws of physics serves as the
glue to tie the various morphological, structural, mechanical,
biochemical and hemodynamic variables (integrate) to make
predictions that can be subjected to experimental validation.
In this brief review, we will consider two examples that
utilize this integrated modeling approach to address physio-
logical/pathological and clinical issues in coronary circula-
tion. On the former, we will consider a model of coronary

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DDMOD-403; No of Pages 7
Drug Discovery Today: Disease Models | Computational models of heart diseases
circulation that predicts the major determinants of trans-
mural coronary blood flow in health and hypoperfusion. On
the latter, we will discuss models of coronary circulation that
predict the fractional flow reserve (FFR) in patients based on
patient-specific coronary anatomy of the coronary lesions
using CT angiography. Future efforts that integrate the two
models to provide non-invasive patient-specific subendocar-
dial FFR may provide greater sensitivity for assessment of
functional severity of coronary lesions.
Anatomically based mathematical models of coronary
circulation
An integrated mathematical model of the coronary circula-
tion requires detailed anatomical and mechanical properties
of the coronary vasculature and the heart, and appropriate
initial and boundary hemodynamic conditions. We previ-
ously measured the anatomy of coronary vasculature using
casts [13] and CT images [4] as well as compliance using
angiography [5,6]. Our group and others have accumulated
abundant morphological (diameter, length, and wall thick-
ness) [13,710] and mechanical [5,6,1114] data of coronary
arterial and venous trees, from the largest vessels to capillar-
ies. The entire 3-D coronary vasculature was reconstructed by
means of global geometrical optimization using simulated
annealing procedures [15,16]. Figure 1 shows a reconstructed
full coronary vascular network with millions of arteries and
veins down to the capillary bed [16].
(a)
(c)
Figure 1. Rendering of reconstructed arterial and venous trees as viewed form four different aspects: (a) anterolateral left, (b) anterolateral right, (c)
posterolateral left and (d) posterolateral right. Orange arterial, cyan venous trees. Reproduced from Kaimovitz et al. [14].
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Based on the detailed anatomical and elasticity data of the
coronary blood vessels, the statistical distributions of pres-
sure, flow, resistance and volume in the branches of the
coronary arterial tree and capillary network have been previ-
ously analyzed in the diastolic heart under steady state flow
conditions [1722]. Most of the pressure drop is found to
occur across the smallest arterioles with diameters <100 mm,
consistent with [23,24], and the flow is heterogeneous with
fractal tree characteristics [25]. One interesting observation is
that the dispersion of pressure and flow are significantly
reduced in the presence of capillary cross-connections with
the flow resistance being reduced as well [19]. An analysis of
pulsatile flow in the coronary arterial tree [26,27] has also
been carried out which predicted a decrease of the phase
angle of flow along the trunk of the major coronary artery and
primary branches towards the capillary vessels in the vaso-
dilated, diastolic arrested heart; in agreement with experi-
mental measurements. An experimental validation of the
spatial flow heterogeneity in an entire coronary 3D arterial
tree using microsphere measurements has also been made
[28]. Figure 2 shows the longitudinal pressure distribution
along the coronary arterial tree in a 3D model of the coronary
arteries [28].
Vesselmyocardial interaction
A major feature of the coronary circulation is the phasic
nature of blood flow where the flow may seize or even reverse
(b)
(d)
Drug Discovery Today: Disease Models
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Vol. xxx, No. xx 2014
(a)
Figure 2. Longitudinal pressure distribution in two views (lateral left and posterolateral oblique left) in the 3D entire coronary arterial trees consisting of
the epicardial, transmural, and perfusion subnetworks: (a) lateral-left-view pressure and (b) posterolateral-oblique-left-view pressure. Reproduced from
Huo et al. [24].
in systole due to vessel-myocardial interaction (MVI). A
recent structure-based analysis demonstrated MVI in a sim-
plified realistic anatomical model of the coronary vasculature
nested in a dynamic model of the heart [29]. The model was
used to test the hypothesis that only a specific combination of
MVI mechanisms can account for all observed coronary flow
features (1). Three basic interaction mechanisms (cavity-in-
duced extravascular pressure, varying elasticity, and shorten-
ing-induced intramyocyte pressure), and their combinations
were analyzed based on physical principles in simplified data-
based vascular and myocardial models. An overview of the
model is shown in Fig. 3.
The model was used to test five mechanical mechanisms:
Cavity Pressure Model (CPM), Varying Elasticity Model, Intra-
myocyte Pressure Model (IPM), CPM + VEM, and CPM + IPM
to determine which model or combination of models is the
most consistent with the phasic velocity and diameter data
measured in the literature. The model predictions of vascular
pressure, velocity and diameter patterns were in agreement
with in vivo measurements only when both the LV pressure
and the myocardial contractility are imposed on the vessel.
This underscores the significance of muscle contractility and
suggests that none of the current hypotheses (systolic extra-
vascular resistance, intramyocardial pump, time-varying ela-
stance, waterfall model, etc.) alone can predict full coronary
physiology [3033]. Rather, a combination of previous hy-
potheses is required to predict the experimental measure-
ments on coronary circulation [29].
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Drug Discovery Today: Disease Models | Computational models of heart diseases
Units (mmHg)
(b)
85~100
70~85
55~70
40~55
26~40
Drug Discovery Today: Disease Models
Subendocardial vulnerability
Based on the MVI model described above, the mechanism of
subendocardial hypoperfusion during ischemia was investi-
gated [34]. Myocardial contractions were found to induce
difference in endo-to-epi trans-vascular pressures (40 mmHg)
and in vascular compliance, due to the non-linear pressure-
diameter relation (PDR) of vessels. Perfusion pressure reduc-
tion from 100 to 40 mmHg reduced the endo/epi perfusion
ratio by 20%. A parametric analysis indicated that this endo/
epi ratio reduction was moderated in the absence of either
cardiac contractions and lack of regional differences in vessel
wall thickness. Subendocardial perfusion was improved with
reduction of either heart rate or LV pressure, especially under
low perfusion pressure. The major conclusion was that sub-
endocardial vulnerability is due to differences in vascular
compliance as induced by regional heterogeneity in both
extravascular loading and vessel wall thickness [9]. The model
suggests that lowering of the heart rate and pressure reduces
the ischemic vulnerability under the same hypoperfusion
pressure, which provides a physiological rationale for the
efficacy of pharmacological interventions that target hyper-
tension and tachychardia [35].
Model-based non-invasive determination of fractional
flow reserve
A fundamental clinical issue in IHD is the determination of
the functional significance of a lesion to justify therapy. A
lesion that is >70% stenotic is typically treated by PCI, while
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Drug Discovery Today: Disease Models | Computational models of heart diseases Vol. xxx, No. xx 2014

(a) Network reconstruction (b) Network Flow model

A V
V
R(t) 2 PIV R(t) 2

Epi C(t)

Endo PEV

(e) Inputs (f) Outputs

* HR

* Contractility Flow * P(t)

* LVP(t) Analysis * Regional Perfusion

* Pperf (t)

(c) Vessel-in-Myocaridium Model (d) MVI mechanisms

Stress-Free PDR
2
LVP
PIV
1.5

Patm
1

-200 0 200
Drug Discovery Today: Disease Models

Figure 3. Schematic representation of the simulation platform. (a) Network anatomy was reconstructed based on statistical morphometric data of
porcine coronary vasculature. (b) Each vessel flow analysis was carried out based on a non-linear analog circuit where PIV and PEV are intravascular and
extravascular pressures, respectively. R and C are the vessel (time-varying) resistance and capacitance, respectively. (c) In situ vessel mechanics was
determined from a non-linear finite deformations stress analysis of the vessel inside a cylinder of myocardium. The analysis accounts for the measured
stress-free configurations of the two cylinders (unloaded and free of residual stress, left panel). Right panel predicted sigmoid pressure-diameter relations
(PDR) in a representative vessel (solid line), and comparison with experimental data (error bars). Dash the linearized PDR of that vessel. X-axis is
transvascular pressure (in mmHg); Y-axis the diameter normalized relative to zero-pressure diameter. (d) Each network vessel was subject to an
extravascular pressure stemming from both left ventricle cavity pressure (LVP, left) and the contraction-induced intramyocyte pressure. (e) Heart rate,
contractility, hematocrit and dynamic left ventricle, perfusion and outlet pressures (LVP, PA and PV, respectively) are inputs. (f) The model predictions were
evaluated in terms of transmural distribution of flow and dynamic transvascular pressures DP. Reproduced from Algranati et al. [25] by permission.

lesions <50% stenotic are only treated medically (drugs). For
intermediate lesions (50-70% stenosis), it is important to de-
termine the functional significance of the lesion on coronary
blood flow determined indirectly through pressure drop mea-
surements under hyperemic conditions. FFR (ratio of maximal
blood flow in a stenotic artery to normal maximal flow mea-
sured as the ratio of distal to proximal pressures at hyperemic
conditions) was introduced [36] to assess the functional sever-
ity of the stenosis by use of a pressure sensor (<0.75 is consid-
ered functionally significant albeit recent recommendations
have raised this value to 0.80). The FAME (I and II) landmark
trials showed a clear benefit of FFR in guiding PCI for better
clinical outcome with cost-effectiveness [3639]. The method
for FFR measurement, however, requires the use of a pressure
wire inserted through the coronary stenosis invasively in the
catheterization laboratory. A noninvasive method to quantify
FFR can streamline patient treatment and eliminate the need
for catheterization in patients with non-physiologically signif-
icant lesions which may have significant impact clinically to
avoid invasive procedures and to reduce healthcare costs [40].
FFR based on computational fluid dynamics
A noninvasive assessment of FFR via combination of compu-
tational fluid dynamics (CFD) and computed coronary to-
mography angiography CCTA (denoted as FFRCT,CFD) has
been recently reported [41,42] as advanced by HeartFlow
(a start-up company that provides FFRCT through a web-
based service; http://heartflow.com/). Recent studies have

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Vol. xxx, No. xx 2014 Drug Discovery Today: Disease Models | Computational models of heart diseases

demonstrated the potential of FFRCT as a promising nonin- (FFRAM) model (real time) and CFD (FFRCFD) for known dimen-
vasive method for identification of individual lesion with sions of lesion was excellent (nearly a perfect identity line with
ischemia from single-center and multi-center prospective R2 = 1) albeit the latter is much more computationally costly
studies [4144]. The cost saving potential of using FFRCT to (>6 hours) [40]. In vitro (constrictions were created in isolated
guide clinical management, in comparison with commonly arteries using symmetric and asymmetric tubes as well as an
used alternative strategies for the diagnosis and treatment of inflatable occluder cuff) and in vivo swine experiments (con-
patients with known or suspected CAD has also been pro- strictions were induced in coronary arteries of swine by an
jected [40]. Hence, a strategy based on use of FFRCT as a occluder cuff) were used to validate the proposed analytical
gatekeeper for interventional coronary angiography and for model. The proposed model agreed very well with the experi-
PCI in a lesion-specific manner may lower costs, because it mental measurements (Figure 4). Flow pulsatility and stenosis
would reduce the rate of these procedures in patients without shape (e.g. eccentricity and exit angle divergence) had a negli-
flow-limiting stenosis. gible effect on myocardial FFR because it is based on a mean
pressure (pulsatility is averaged out) and Reynolds number is
Analytical model of FFR small (<100, and hence the detailed shape of the lesion is
The FFRCT requires around 6 hours for the CFD/finite element unimportant), while the entrance effect in a coronary stenosis
model (FEM) analysis to converge, however, and a real-time was found to contribute significantly to the pressure drop
computation of FFR is desirable. We recently developed a new which is accounted for in the analytical model [48].
analytical model (AM) to quantify pressure drop, and hence
FFRAM, based on the dimension of lesion (i.e. the cross-section- Limitations of current models and future works
al area along the lesion and the length of lesion) and coronary Although the models of coronary circulation are based on
flow with no empirical parameters unlike previous models extensive measured anatomical and elasticity data, more
[4547], and validated it using in vitro and in vivo experiments morphometric data are needed. The transmural variation
and CFD (Fig. 4) [48]. Agreement between the analytical of anatomy is needed beyond the transmural variation in

(a) T-junction connected with pressure transducer (b) T-junction connected with pressure transducer

Sutured against
vessel wall Tubing inside of vessel

Tubing
Occluder Flow direction
Adapter to control inside
Flow direction Adapter to Carotid artery
pressure of vessel Pump
Pump control pressure
Cross-sectional area of Cross-sectional area of
symmetric stenosis asymmetric stenosis
Carotid artery
(c) (d) 40 (e)
60 1.0 CSAstenosis CSAproximal

50
75%

0.9
30
Pexperiment (mmHg)

Pexperiment (mmHg)

40 0.8
FFRexperiment

area stenosis > 75%

30 20 0.7

20 0.6
10
10 0.5

0.4
0 10 20 30 40 50 60 0 10 20 30 40 0.4 0.5 0.6 0.7 0.8 0.9 1.0
Ptheory(mmHg) Ptheory(mmHg) FFRtheory

Drug Discovery Today: Disease Models

Figure 4. A schematic representation of in vitro stenosis set-up: (a) insertion of known sizes of concentric and eccentric tubings into an artery to mimic
various stenoses; (b) an arterial occluder to create various stenosis; (c) a comparison of pressure gradient between theoretical model and in vitro artery
experiments (DPtheory and DPexperiment) using symmetric (square) and asymmetric (triangles) tubings as well as an inflatable occluder cuff (asterisks).
FFRtheory corresponds to FFRAM. Modified from Algranati et al. [36] by permission.

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Drug Discovery Today: Disease Models | Computational models of heart diseases
wall thickness recently measured [9]. The majority of the
compliance data (with the exception of the largest several
orders [5]) has been determined in isolated vessels which does
not account for the surrounding tissue. The passive and active
effect of surrounding tissue on smaller vessels has yet to be
determined experimentally. In addition to passive compli-
ance data, a systematic database on vasoreactivity of small
coronary arteries is necessary that includes potential trans-
mural effect. The advancement of entire models of coronary
circulation based on anatomically accurate 3-D coronary
vascular anatomy, vasoreactivity and subject-specific cardiac
anatomy including vessel elasticity and cardiac electro-me-
chanics in the beating heart are still needed. These models
can help predict and explain chamber, spatial layer and
within layer heterogeneity of blood flow in health and ische-
mia. The models can also demonstrate the casualty between
spatial heterogeneity of work rate of myocardium and oxygen
consumption and the observed flow heterogeneity in normal
and ischemic myocardium.
The underlying assumption in the calculation of FFRCT that
the microcirculation of patients is normal may not be true. We
have developed and validated scaling laws that relate morpho-
metric parameters (e.g., lumen diameter and area, vessel length
and volume, etc.) to coronary blood flow [4953] and myocar-
dial mass [54]. These structure-function relations can be used to
determine the flow on a patient-specific basis given the specific
anatomy and myocardial mass as obtained from CCTA (coro-
nary flow cannot be directly measured from CCTA). This can
address the limitation of a constant empirical resistance for the
coronary microvasculature in order to estimate the patient-
specific flow through the coronary vasculature [44]. Further-
more, the results cannot be obtained in the clinic but require an
offsite service to provide the FFRCT,CFD. These issues diminish
the utility of FFRCT,CFD and this needs to be addressed in future
works. In addition to the use of computationally efficient
models, there is also a need for accurate (validated) and efficient
and segmentation algorithms for the reconstruction of patient
coronary anatomy from CT images. Our group has recently
developed a validated semi-automated segmentation algorithm
for reconstruction of coronary anatomy from CCTA in both
animal models [4] and patients [55]. Clearly, there is a need for
additional major advancements in this regard. Overall, it would
be ideal to implement an in clinic software that can provide
patient-specific FFRCT within one hour on a standard computer.
The model of coronary vasculature coupled with cardiac
mechanics has not only been used to understand transmural
flow and hence the basis for subendocardial vulnerability
under hypoperfusion but it has also been used to understand
the limitations of FFR in relation to compliance of the vascu-
lature [56]. This has implications for patients with stiffer
coronary vasculature (diabetics, smokers, hypertensive
patients, etc.). A future extension of the model can be used
to evaluate transmural FFR and, in particular, subendocardial
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FFR as a more sensitive index of ischemia than the global FFR
currently used in the clinic. Algranati et als model [56] showed
the FFR value (ratio of flows) based on total flow is generally
higher than the respective FFR based on transmural flow values
which implies that the expected improvement in subendocar-
dial flow due to a coronary intervention is higher than in the
total coronary flow. This prediction agrees with the known
vulnerability of subendocardium to ischemia [35]. Since ste-
nosis compromises subendocardial flow to a higher extent
than subepicardial flow [57], treatment of stenosis should
improve subendocardial flow even more than total flow.
Conclusions
Mathematical models based on physical principles informed
by subject-specific data have provided both insights into
coronary physiology/pathophysiology as well as enabled
non-invasive tools for diagnosis of IHD. On the former, the
approach has demonstrated that both left ventricular pres-
sure and myocardial contractility are important determinants
of vessel myocardial interaction and subendocardial vulner-
ability stems from the differences in coronary compliance as
induced by regional heterogeneity in extravascular loading
(LV pressure and myocardial contraction). On the latter,
patient-specific imaging (e.g., coronary CTA) and computa-
tional fluid dynamics has allowed a non-invasive determina-
tion of fractional flow reserve for assessment of functional
severity of IHD. Future integration of these models to provide
more sensitive indices of subendocardial ischemia is a laud-
able goal for the future. The evolution of patient specific
cardiac modeling based on diagnostics of the heart, coronary
vasculature, electrophysiology, hemodynamics, as well as
other measurable patient specific parameters is an exciting
area with significant clinical applications in Cardiology.
Acknowledgements
This work was supported by grants from the National Insti-
tutes of Health HL117990 and U01HL118738.
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j.ddmod.2014.06.002
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