The Assessment of Large and Small Artery Elasticity for the Early Detection of Cardiovascular Disease
The Assessment of Large and Small Artery Elasticity for the Early Detection of Cardiovascular Disease
Efforts to identify individuals at a higher risk for adverse cardiovascular outcomes focus on
 traditional risk factors, such as age, gender, smoking status, blood pressure, and
 cholesterol; however, this approach does not directly assess cardiovascular function and
 underestimates the risk of experiencing adverse cardiovascular outcomes in women. This
 prospective, observational trial will examine the ability of the Assessment of Large and
 Small Artery Elasticity for the Early Detection of Cardiovascular Disease screening protocol,
 a series of non-invasive procedures to identify middle-aged and older women who are at
 elevated risk for experiencing an adverse cardiovascular event in the five-year period after
 screening. The predictive value of the Assessment of Large and Small Artery Elasticity for
 the Early Detection of Cardiovascular Disease protocol will also be compared to the
 Framingham Risk Score to determine if one method has better sensitivity for estimating risk
 for an adverse cardiovascular outcome.
Every seven minutes in Canada, there is a death due to heart disease or stroke. Up to 80% of
 cardiovascular disease (CVD) could be prevented by identifying and controlling for biological
 risk factors such as hypertension, high cholesterol, and diabetes, and behavioral risk
 factors such as physical inactivity, unhealthy diet, and smoking. Efforts to identify
 individuals at a higher risk for adverse cardiovascular events, such as the Framingham
 Disease Risk (FDR) score, focus on traditional risk factors, such as age, gender, smoking
 status, blood pressure, and cholesterol. While this approach does estimate 10-year risk for
 heart attacks,3 it remains suboptimal as it does not assess how well each individual's
 cardiovascular system is functioning. In fact, a previous study suggests that more than 80%
 of females evaluated with the FDR were identified as being at low risk, or not qualifying for
 medications known to lower cardiovascular risk before experiencing a myocardial infarction.
 Therefore, these data warrant the use of cardiovascular screening approaches that are more
 accurate in identifying the risk of adverse cardiovascular outcomes.

 There is a common perception that CVD is a 'man's disease'; however, women tend to develop
 heart disease approximately 10-15 years later than men, with a prevalence rate similar
 between sexes after ≥ 60 years of age. Heart disease is the leading cause of death in women
 worldwide. Women are often under-represented in cardiovascular clinical trials, which is an
 issue because their clinical presentation and prognosis of cardiovascular disease differs
 from that of men. In fact, women who suffer an acute MI are more likely to die, have an
 increased risk of repeat MI, develop heart failure, or consequentially suffer sudden cardiac
 death, as compared to men. Although improvements in CVD management have led to decreased
 mortality rates, more women than men have died from causes related to CVD since 1980. It is
 also important to highlight that traditional risk factors assessed by FDR score underestimate
 the risk of experiencing an adverse cardiovascular event in women, as compared to men. Thus,
 it appears that there is a need to develop innovative screening tools to better detect early
 stages of CVD risk amongst women.

 The Assessment of Large and Small Artery Elasticity for the Early Detection of Cardiovascular
 Disease trial is a screening program designed to screen for cardiovascular risk in women. It
 was adapted from the 4-Test Rasmussen cardiovascular screening program, which was developed
 by Dr. Jay Cohn at the Center for Cardiovascular Disease Prevention, University of Minnesota.
 The 4-test screening approach utilizes non-invasive procedures to measure structural and
 functional changes in the large and small arteries, including elasticity of artery walls and
 blood pressure at rest and in response to 3-min of moderate intensity exercise. Tests are
 scored from 0-2 (0 = normal; 1 = borderline; 2 = abnormal) with a total RDS ranging from 0-8.
 Each participant is categorized based on risk (i.e. 0-2 = normal; 3-8 = abnormal). These
 simple, non-invasive procedures aim to detect early stages of CVD for individual asymptomatic
 patients. However, these tests are not yet available in the primary care setting and have not
 been used in a Canadian clinical context. Moreover, it is not known if this screening
 approach and other protocols are feasible and have sufficient predictive value within the
 context of the Canadian health care system, where health services in Canada are generally
 delivered by the private sector but funded by payments from provincial health insurance. The
 more comprehensive 10-test Rasmussen Disease Score (RDS), which uses, in addition to the
 4-test approach, optic fundus imaging, a resting electrocardiogram, an ultrasound of the left
 ventricle and abdominal aorta, microalbumin, and brain natriuretic peptide, is better than
 the FDR at identifying individuals at risk for experiencing adverse cardiovascular events
 within 3-5 years.10 However, it is unknown whether the 4-test RDS (which will hereon in be
 referred to the Assessment of Large and Small Artery Elasticity for the Early Detection of
 Cardiovascular Disease protocol) is a better predictor of future cardiac events than the FDR
 in women. It is also unknown if the Assessment of Large and Small Artery Elasticity for the
 Early Detection of Cardiovascular Disease screening protocol can predict future adverse
 cardiovascular events in women.

 This prospective, observational study aims to: 1) determine if the Assessment of Large and
 Small Artery Elasticity for the Early Detection of Cardiovascular Disease screening protocol
 identifies middle-aged and older women who are at an elevated risk for experiencing adverse
 cardiovascular outcomes within a five-year period after screening; and, 2) compare the
 sensitivity and specificity value of the Assessment of Large and Small Artery Elasticity for
 the Early Detection of Cardiovascular Disease protocol and the FDR for predicting future
 adverse cardiovascular outcomes in women. The investigators hypothesize that the Assessment
 of Large and Small Artery Elasticity for the Early Detection of Cardiovascular Disease
 protocol will provide better diagnostic accuracy in identifying middle-aged and older women
 at an elevated risk for experiencing adverse cardiovascular outcomes in the five year period
 post-screening, as compared to the FDR.

 The Assessment of Large and Small Artery Elasticity for the Early Detection of Cardiovascular
 Disease Protocol:

 After patient enrollment and consent, the Assessment of Large and Small Artery Elasticity for
 the Early Detection of Cardiovascular Disease protocol required participants to attend one
 appointment, which was scheduled for approximately 90 minutes. The Assessment of Large and
 Small Artery Elasticity for the Early Detection of Cardiovascular Disease protocol involves
 four measurements, as follows: 1) resting blood pressure; 2) systolic blood pressure response
 to 3-min of moderate intensity exercise; 3) large artery elasticity assessment; 4) small
 artery elasticity assessment. For these measurements, the HD/PulseWave™ CR-2000 Research
 CardioVascular Profiling System (CV profiler) was used. This device is indicated for use in
 determining cardiovascular parameters in human subjects for research purposes only. Research
 staff were trained in the use of the HD/PulseWave™ CR-2000 Research CardioVascular Profiling
 System and performed all of the testing. Below each of the measures involved in the
 Assessment of Large and Small Artery Elasticity for the Early Detection of Cardiovascular
 Disease protocol are described.

 Test 1: Resting blood pressure A blood pressure cuff attached to the CV profiler is placed on
 the participant's arm while they are in a supine position. A resting blood pressure of less
 than 120/80 mmHg is considered normal (0 RDS points), 120-139/80-89 is considered
 pre-hypertensive (1 RDS point) with the potential for the development of high blood pressure
 (hypertension). Blood pressure greater than 140/90 is considered abnormal for adults (2 RDS
 points).

 Test 2: Systolic blood pressure response to exercise The magnitude of rise in blood pressure
 during exercise may be an indication of early risk for developing hypertension, even if the
 participant's resting blood pressure is normal. After the resting blood pressure is assessed,
 the participant is asked to perform 3 minutes of moderate exercise on a 2-step stool
 according to the Dundee Step Test, or on a treadmill for those who are unable to perform the
 step test. Both of these exercise procedures are performed at a 5 metabolic equivalent (MET)
 workload. The participant then has their blood pressure measured once again in a supine
 position immediately following the exercise protocol. A rise in systolic blood pressure of
 under 30 mmHg and less than 169 mmHg absolute blood pressure is considered normal (0 RDS
 points), a rise of 30-39 mmHg and an absolute resting blood pressure of 170-179 is considered
 borderline (1 RDS point), and a rise of 40 mmHg or more and an absolute resting blood
 pressure of 180 mmHg or high is considered abnormal (2 RDS points).

 Test 3 and 4: Large and small artery elasticity To measure artery elasticity a wrist
 stabilizer is placed on the participant's wrist while they are in a supine position. A
 piezoelectric transducer, or pulse wave sensor, is then placed on the location of strongest
 pulsation of the radial artery adjacent to the styloid process. The CV Profiler assesses the
 diastolic decay and waveform transmitted to it through the sensor. Based on the modified
 Windkessel model, the instrument can then determine small artery and large artery elasticity.
 Measures from this instrument have been shown to be reproducible, with one studying finding
 that intra-visit measurements five minutes apart only differed by 3% and inter-visit measures
 one to four weeks later only differed by 4%. Scoring of normal, borderline and abnormal
 results for large and small arterial elasticity are based on age and gender cutoffs.

 Scoring the Assessment of Large and Small Artery Elasticity for the Early Detection of
 Cardiovascular Disease protocol:

 Each of the tests in the 4-test RDS are scored as 0 for normal, 1 for borderline abnormal,
 and 2 for abnormal10. Total scores range from 0 to 8 and are used to stratify individuals
 into one of two risk groups: 0-2 = normal risk; ≥ 3 = moderate to high (abnormal) risk.

 Assessment of the Framingham Risk Score:

 FDR is determined based on the calculations described by D'Agostino et al. Information
 required for this calculation is acquired from a participant questionnaire, fasting blood
 sampling of high density lipoprotein and total cholesterol, and the resting blood pressure
 reading from the CV Profiler. Participants are asked to fast for the 12 hours prior to the
 blood draw at their appointment. Approximately 10 mL of blood is collected by a phlebotomist.
 The samples are then centrifuged so that the plasma can be separated and analyzed for total
 cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides, and fasting
 glucose.

 Exploratory testing:

 A battery of additional validated cardiovascular related testing will be conducted in
 addition to the previously mentioned tests. Exploratory statistical analyses will examine
 different combinations of these test results combined with the resting blood pressure,
 exercise blood pressure response and arterial elasticity results in an attempt to improve the
 sensitivity and specificity of the Assessment of Large and Small Artery Elasticity for the
 Early Detection of Cardiovascular Disease screening protocol.

 Questionnaires

 Participants are instructed to fill out a series of questionnaires:

 1. physical activity behaviour is assessed using the International Physical Activity
 Questionnaire (IPAQ) short-version. This questionnaire measures the amount and intensity
 of physical activity completed by an individual;

 2. the Cardiovascular Health in Ambulatory Care Research Team (CANHEART) Health Index is
 used to assess cardiovascular health behavior and disease risk based on physical
 activity (from the IPAQ short-version), smoking status, fruit and vegetable consumption,
 body mass index, as well as presence of diabetes and high blood pressure;

 3. stage of change for health behaviors and stages of change specifically related to
 physical activity are assessed using the Transtheoretical Model of Change and the
 Physical Activity Stages of Change questionnaires, respectively;

 4. quality of life is assessed using the EuroQol Five Dimension Five Level questionnaire;

 5. presence and severity of depressive symptoms are assessed using the Patient Health
 Questionnaire-9.

 Fried Frailty Phenotype A phenotype of frailty was assessed using the Modified Fried Criteria
 as previously described by Fried et al. Briefly, the Fried score classifies participants as
 frail if three or more of the following criteria are met: 1) unintentional weight loss; 2)
 self-reported exhaustion; 3) weakness; 4) slow walking speed; 5) low physical activity.
 Exhaustion is assessed by the Center for Epidemiologic Studies - Depression Scale. Physical
 activity levels are assessed by the Paffenbarger Physical Activity Scale23. Unintentional
 weight loss is determined via a questionnaire, while the weakness and slow walking speed are
 assessed using a grip strength dynamometer and a five meter gait speed test, respectively.

 6- Minute Walk Test Participants are instructed to walk as many lengths of a 30 meter track
 as possible during the 6 minute duration. Distance covered during the test is recorded. A
 study by Beatty et al. showed the prognostic value of the 6MWT for predicting cardiovascular
 events in patients with stable coronary heart disease.

 Adverse Cardiovascular Outcomes - 5-year follow-up Upon completion of the Assessment of Large
 and Small Artery Elasticity for the Early Detection of Cardiovascular Disease Protocol, each
 individual's Personal Health Information Number (PHIN) will be utilized to follow the study
 participants and to determine if they experienced an adverse cardiovascular outcome, as
 defined in Table 2, using the Manitoba Centre for Health Policy (MCHP) Population Health
 Research Data Repository. This linkage will be done at Manitoba Health, which will provide
 MCHP with the correct scrambled identifiers needed to follow-up all participants. MCHP data
 will be accessed through a number of different databases. Hospital separations abstracts,
 medical claims and the Drug Program Information Network will be examined to provide
 information on hospitalizations for cardiac diseases, cardiac procedures performed,
 cardiac-related and other medications used, and diagnoses with cardiac diseases. This
 information will help examine the diagnostic accuracy of the RDS versus the FDR. Vital
 statistics will also provide information on cause of death to allow for mortality rate
 tracking. This administrative health data will be used to compare adverse cardiovascular
 events with the Assessment of Large and Small Artery Elasticity for the Early Detection of
 Cardiovascular Disease protocol results to determine if this cardiovascular screening
 approach predicted which individuals were at moderate to high risk of an adverse
 cardiovascular outcome over the five-year period after screening. The investigators'
 rationale to access all follow-up health information from the Repository at the MCHP is to
 obtain the most accurate information on healthcare service utilization, adverse
 cardiovascular events, demographics, etc. This method is much simpler, more complete and less
 invasive than repeated contact with participants.

 Statistical analysis Based on published data, the investigators predict that 36% of the
 screened population (i.e. 360 of the 1000 participants) will have an abnormal outcome based
 on the Assessment of Large and Small Artery Elasticity for the Early Detection of
 Cardiovascular Disease Protocol (i.e. a score of 3 or greater). This data indicates that
 approximately 7.7% (i.e. 28 of the 360 participants) of the people with an abnormal score
 will experience an adverse cardiovascular outcome in the 5-year period. Kaplan-Meier methods
 and Receiver Operating Characteristic curves will be conducted to estimate cumulative rates
 of adverse outcomes and to compare the sensitivity and specificity of the Assessment of Large
 and Small Artery Elasticity for the Early Detection of Cardiovascular Disease protocol and
 the FDR score, respectively. A Cox Proportional Hazards model will be conducted, controlling
 for covariates identified through univariate analysis, such as age, that could be predictive
 of adverse cardiovascular outcomes.
Inclusion Criteria:

 -  women aged 55 and older

 -  possess a Manitoba Personal Health Information Number

 Exclusion Criteria:

 -  previous hospitalization for:

 -  ischemic heart disease

 -  acute myocardial infarction

 -  stroke

 -  percutaneous coronary intervention

 -  coronary artery bypass surgery

 -  congestive heart failure

 -  peripheral artery disease