«Detection of coronary artery disease with an electronic stethoscope Schmidt, Samuel Publication date: Document Version Publisher's PDF, also known as ...»
Cardiovascular disease, which includes CAD, constitutes a major global health problem and is the leading cause of death in the world. In 2004 cardiovascular disease accounted for 29% of all death . CAD is the cardiovascular disease which accounts for most deaths and CAD accounts for 12.3% of all deaths worldwide . In Europe more than 20 % of all deaths were caused by CAD in 2000  and the CAD prevalence in Europe was 9.9 million. Figure 1 show the US prevalence distributed according to age and gender. In 2002 the worldwide prevalence of CAD was 40 million and the total number of deaths caused by CAD was 7.2 million .
Figure 1. Prevalence of CAD in the USA by age and sex (2003-2006) .
In recent years CAD mortality has declined in the US and Western Europe. For example, CAD mortality decreased with 42 % in the United Kingdom from 1994 to 2004 . The decrease in death rate is due to a lower rate of heart attacks and a better chance of surviving a heart attack . Also the incidence rate is declining in Western and Northern Europe. Even though the mortality has been declining in Western countries a future increase in CAD mortality is expected due to the aging population . The decline observed in western counties is in sharp contrast to the increases in CAD mortality in developing counties. From 1990 to 2020 CAD mortality in developing counties is expected to increase with more than 120% . Already today 82% of all CAD related deaths is occurring in the developing countries .
1.2. Diagnostic challenge The first manifestation of CAD is either acute (MI and unstable angina) or non-acute (typical Stable angina). The typical diagnostic process of diagnosing CAD in the nonacute phase starts with a risk assessment based on symptoms, medical history and risk factors. Typical risk factors include family history of CAD, age, sex, smoking, abnormal blood lipid levels, hypertension, diabetes mellitus, abdominal obesity, low daily fruit and vegetable consumption and lack of Physical activity [2, 3]. Based on the risk assessment the patient might be referred further to diagnostic testing or a risk reducing treatment might be started. The choice of diagnostic test is ideally based on the patient’s CAD risk, the accuracy of the test, the cost of the test and risk of the test.
Common methods for diagnosis of CAD include Coronary angiography, CT coronary angiography, ECG stress test, Stress Echocardiography and Myocardial Perfusion Imaging. Table 1 shows cost and performance of the different diagnostic methods. The cost estimates are based on the 2010B Medicare Physician Fee Schedule .
Table 1. Performance and cost (Medicare Physician Fee) of common methods for diagnosis of CAD.
[5, 9, 10]
The accuracy of Coronary angiography is high and Coronary angiography is considered the golden standard for the diagnosis of CAD and is used as a reference test in validation of other methods . The disadvantages are that the method is invasive, costly, requires highly trained personnel, constitutes a risk of complications  and that the method exposes patients to radiation .
Computed tomography (CT) coronary angiography is under heavy development and is predicted to play an important role in the diagnosis of CAD. The advantage is that the method is noninvasive and has a relative high accuracy. A recent Meta analyses found that the sensitivity was 97% and specificity 87% . Drawbacks are high cost, radiation  and that in case of a positive test Coronary angiography is needed for the percutaneous transluminal coronary angioplasty procedure, thereby the patient is exposed to the double amount of radiation.
The ECG stress test is the simplest CAD test. The advantages are low cost and that the test result is directly related to cardiac functionality. The disadvantage is low accuracy, sensitivity is 68% and specificity is 77% .
The Echo stress test is an expansion of the ECG stress test by analyses of changes in the ventricular movement under stress such as exercise. The advantage is an improved accuracy, but drawbacks are a high operator variance and that the method requires highly trained personnel.
Myocardial Perfusion Imaging is often used in combination with cardiac stress induced by exercise or pharmacologically induced. The benefits of Myocardial Perfusion Imaging are mapping of the dysfunctional myocardium. Drawbacks are radiation and high cost.
In spite of the broad range of tests, the diagnostic challenge remains. Three diagnostic
challenges are outlined below:
A high number of referrals with negative coronary angiography results.
A recent study of American College of Cardiology National Cardiovascular Data Registry showed that only 41% patients without known history of CAD referred for coronary angiography suffered from obstructive coronary artery disease . Obstructive coronary artery disease was defined as having at least one stenosis with a minimum of 50% diameter reduction. The authors of the study concluded that better strategies for risk stratification are needed to reduce the number of negative coronary angiographies . This will include a better application of noninvasive tests.
Asymptomatic CAD is common. Approximately 15 % of MI events in US are fatal  and it is estimated that worldwide 39% of the MIs are fatal . It is therefore essential to diagnose CAD before the progression to the acute state . However only 18-43 percent of coronary attacks are preceded by angina [3, 13]. Statistics shows that 50% of men and 64% of women who die suddenly of CAD have no previous symptoms of the disease . Identification of CAD patients can thereby not be based on symptoms alone. Proposed approaches include noninvasive testing of subjects with high risk .
Low-cost diagnostic methods are needed in developing counties. The increases in CAD prevalence in developing counties will require affordable and fast to use diagnostic tests .
A low-cost and low-risk test, preferably with a higher accuracy than the ECG stress test, would properly improve the risk stratification before referral to coronary angiography and thereby reduce the number of negative coronary angiography results.
In addition a low-cost and low-risk diagnostic method would allow an expanded screening of patients with an intermediate to high risk of CAD. The goal of the current thesis is to develop such a low cost and easy to use CAD test using an electronic stethoscope. An electronic stethoscope based method would be low cost, low risk, easy to use and rapid. Such a method will be suited for use in the early diagnostic phase, for example in the first patient encounter with the primary care physician.
1.3. Physiology and the signature of murmurs
The rationale behind acoustic based diagnosis of CAD is that atrial constriction causes turbulent blood flow in the poststenotic region. The turbulence generates noise, the so called Murmurs or Bruits. Cardio vascular murmurs are common pathological indicators. Typical murmurs originate from the heart valves, the carotid arteries and the renal arteries. Audible CAD murmurs are rare, but reported in several case studies [16The scope of signal processing algorithms for detection of CAD is to develop methods which identify the CAD murmurs even though they are non-audible.
Whether linear flow transitions to turbulent flow or not depends on the Reynolds 1 (Re) number and on the geometry of the channel leading the flow. Figure 2 is a model of a stenosis constricting an artery. In the figure d denotes the diameter of the stenosis and D the vessel diameter. Throughout the thesis the degree of stenosis will be defined by the percentage-wise diameter reduction 100x(1-d/D) caused by the stenosis. At slow flow rates the blood will be fully laminar and the blood will follow the artery boundaries immediately after the stenosis, but as the flow rate increases (Re~10) separation will occur and a jet will originate from the stenosis orifice . The jet will collide with the slowly moving blood in the outer region of the artery and eddies will occur in the sides of the artery close to the stenosis orifice. As flow increases instability will occur and the post stenotic flow will become turbulent .
1.3.1. The coronary anatomy The coronary artery tree consist of three major arteries the right coronary artery (RCA), the left anterior descending (LAD) and left circumflex artery (LCX). Both the LAD and LCX originate from the left main coronary artery (LMCA). The RCA originates from the aorta. Typically, the LAD supplies the anterior parts of the left ventricle and septum, and the whole apex. The LCX supplies the left atrium, the lateral free wall and the posterior side of the left ventricle. The RCA supplies the right side of the heart, the inferior part of the left ventricle and the posterior part of the septum. In an anatomical study the outer diameters of the proximal segments of the LMCA, RCA, LAD and LCX arties in men were respectively 4.5±0.5 mm, 3.9±0.6 mm, 3.6±0.5 mm and
3.4±0.5 mm . Diameters of the most distal segments of RCA, LAD and LCX were
3.1±0.5 mm, 1.7±0.5 mm and 1.6±0.6 mm. On average, in women the arteries were 14% narrower than in men.
1.3.2. Coronary flow Due to the strong systolic myocardial contraction, the left coronary flow usually peaks in the diastolic period, see Figure 4. However in cases of severe CAD the balance between myocardial and arterial resistance is altered and the diastolic flow will decline more than the systolic flow. The flow rate varies widely from artery to artery and from subject to subject. A weighted average calculated from several studies of CAD patients showed an average coronary flow velocity in the major arteries at 20.3 cm/s and an average standard deviation at 7.8 cm/s [24-30]. There was no difference between resting flow velocities in the three major arteries [28, 31]. The peak diastolic flow was approximately 1.5 times higher than the average flow velocity [24, 27, 29]. For a 3 mm blood vessel with 20.3 cm/s blood flow the Reynolds number is 191 (the dynamic viscosity of blood =1/30 poise and density of blood 1.05 g/cm3) this corresponds to findings by Hikita et al. who found an average Reynolds number at approximately 190 (STD: 67) in stenosed arteries. The peak diastolic Reynolds number might therefore reach to 284 in an average patient.
Figure 4. Normal coronary flow pattern recorded using a Doppler catheter .
The hemodynamic effect of the resistance caused by the stenosis is a pressure drop across the stenosis, but in resting conditions the pressure drop across a mild or moderate stenosis is not significant compared to the resistance in the arterioles and the myocardium . Furthermore vasodilatation of the arterioles and increased blood pressure attempts to compensate for the increased resistance across the stenosis.
Typically a 75-85% diameter reduction is necessary to influence the coronary flow rate when the patient is at rest , see Figure 5.
Figure 5. A typical relation between stenosis degree and coronary flow  1.