The CAD Challenge

At a Glance

• Coronary artery disease (CAD) is more often overlooked in women than in men, due to differences in symptoms and disease characteristics
  
• Current imaging and catheterization tools can lead to overtesting in women at low risk and undertesting in women at higher risk for CAD
  
• Researchers have developed an algorithm that examines patients’ age, sex and the expression of multiple CAD-associated genes
  
• The algorithm, called ASGES, has been clinically validated in multiple trials and appears to be more sensitive than the current testing gold standard

The concept that diseases can present differently in men and women is fast gaining traction, among doctors and in the general public. There are numerous articles and infographics circulating around the Internet that illustrate, for example, the difference between heart attack symptoms experienced by men and by women. But recently, a panel of experts from a wide variety of specialties – cardiology, medical technology, personalized medicine, women’s health, patient advocacy, health economics and even payers – convened at the Heart House (Washington, DC, USA) to discuss a less publicized topic: the diagnosis of coronary artery disease (CAD) in women (1).

CAD and related disorders are the leading cause of morbidity and mortality in both sexes, but because women’s symptoms are so variable and so different, diagnosis of such disorders in female patients is a real challenge. The expert panel determined that physicians have difficulty with diagnosis because women present with atypical symptoms and a lower probability of disease, have fatty tissue in the breast area that can lead to false positives in cardiac imaging, and women are more likely to present with difficult-to-identify microvascular CAD. The challenges to spotting CAD have historically meant that doctors rely on a progressive testing pathway that begins with noninvasive imaging for women deemed to be at low risk of disease, with more intensive examinations, such as invasive coronary angiography (ICA), in those at higher risk. But this ends in a testing catch-22: because of the diagnostic uncertainty of imaging procedures, women with a low likelihood of disease are being tested too much, exposing them to risks and complications – while those with a higher likelihood who get false negatives from imaging tests may never receive the more extensive examinations that would accurately indicate the presence of disease.

Much like the problem itself, the potential solution is multi-faceted; clinicians need improved understanding of sex-specific differences in the pathophysiology of CAD, whereas patients need to be aware of the differences between men’s and women’s symptoms. Health care providers – from doctors to payers – should be educated about the risks and benefits of imaging tests, and the when it might be necessary to perform additional tests. They should also be aware of new advances in CAD testing, and in particular new forms of genomic testing that can overcome the challenges of current methods. The expert panel also proposed that doctors incorporate a new age, sex and gene expression score (ASGES) assay into their evaluations of patients with potential obstructive CAD.

Symptom conundrum

Although females constitute about half of the world’s population, many more women than men die of heart disease each year – a trend that, at least in the United States, has been the case for the past 30 years (2). Although the risk of death from heart disease is greater than that of breast cancer for women at all ages, their risk of CAD becomes even greater as they undergo menopause, a factor that only increases concern for the nearly 650 million women in the world over 55 (3). Unfortunately, the gold standard of diagnostic testing – the progression from exercise electrocardiography and myocardial perfusion imaging to diagnostic catheterization – often results in false negative results or in unnecessary invasive procedures and the risks associated with them. It’s clear that better testing methods are needed to exclude patients at low risk of cardiac disease from invasive tests, saving time and money and ensuring that the true root causes of their symptoms are investigated as soon as possible.

One reason women are so often overlooked is that the atypical symptoms of CAD are more subtle. For instance, many patients at risk of heart disease are taught to be aware of pain or pressure in the chest, neck, shoulder, arm, back or jaw. They’re warned that they might experience a pounding or arrhythmic heartbeat, abdominal pain, nausea, dizziness and cold or clammy skin. But women’s symptoms tend to be more difficult to recognize; while they might feel an unusual sensation or mild discomfort, it’s typically not even accompanied by chest pain at all. Women with angina frequently report weakness, shortness of breath, fatigue, nausea or indigestion – but without chest pain, many don’t realize that their symptoms are indicative of a cardiovascular issue. To add to the confusion, men experience a linear relationship between age and CAD prevalence, but in women, the onset of the disease is delayed until perimenopause, then accelerates to a similar rate as is seen in men. Even the biology of the disease is different – men more often present with atherosclerotic plaque, whereas women are more likely to have smaller arteries and fewer lesions, leading to frequent false positives in most common diagnostic tests for CAD.

Solved with a blood test?

Knowing that the current CAD testing methods are all either risky or only moderately effective, a group of scientists from across the United States developed a minimally invasive blood test to reliably assess a patient’s likelihood of obstructive CAD. The study involved two cohorts of case and control pairs matched for age and sex; the first cohort was taken from the Duke University CATHGEN registry, a retrospective blood repository, and the second from the PREDICT (Personalized Risk Evaluation and Diagnosis in the Coronary Tree) study of patients referred for coronary angiography. After the researchers applied microarray analysis to select genes for further investigation (based on a combination of statistical significance, biological relevance, and prior association with CAD), they performed RT-PCR on the 113 chosen genes and used them to develop an algorithm for CAD assessment. The final algorithm focuses on age, sex and the expression of 23 genes, 20 of which were determined to be CAD-associated and three of which serve as normalization genes (4).

Not only does the ASGES algorithm allow the reliable determination of obstructive CAD risk based only on a patient’s age, sex, and a single whole blood draw, but it even highlights sex-specific differences in CAD-associated gene expression. Most of the genes involved in the test correlate with either the lymphocyte or the neutrophil fraction; those in the neutrophil fraction display strong expression differences – 95 percent of neutrophil genes were upregulated in men, whereas in women, 98 percent were downregulated. Findings like this reinforce gender-based differences in CAD pathophysiology and fit well with previous research, including the fact that increased granulocyte counts correlate with higher CAD risk in men, but not in women (5,6). The algorithm was validated in two large-scale studies, PREDICT and COMPASS (Coronary Obstruction Detection by Molecular Personalized Gene Expression) (7,8). In both, ASGES was an independent predictor of obstructive CAD in both males and females, with a higher sensitivity (89 percent) and negative predictive value (96 percent) than myocardial perfusion imaging for the detection of CAD. Now, over 1,000 patients have been examined using the algorithm, and the differences in referral rates for downstream testing have been significant, especially in women – not only are fewer patients sent for additional testing, thus lowering costs and reducing the risk of complications, but the rate of major cardiovascular events during follow-up is lower as well.

Diagnostics should provide doctors with reliable results that inform their clinical decisions and improve outcomes, ideally with minimal risk to the patient. But neither imaging nor catheterization meets those needs: in the case of CAD the former is too inconclusive, the latter too invasive, especially when applied to patients who are unlikely to have the disease. The requirement for a low-risk, high-return test is clear – and ASGES ticks many boxes. This is good news for anyone being evaluated for CAD, but nowhere are the benefits so clear as for women, who may finally have a test that meets their unique needs.