Series Overview:  GenomicMD’s Deep Dive blog series is designed as a casual guide on the journey to better understanding the many details associated with medical conditions on our test panels. Our hope is that this knowledge empowers our readers to start conversations with their healthcare teams about taking proactive measures that can lead to longer and healthier lives. If this sounds interesting to you, please read along as we dive deeper into the subject of heart disease (Coronary Artery Disease, or CAD, in particular) and learn more about its biology, symptoms, genetic links, and impact on the human body. 

**Please note that our Deep Dives blog series is not intended to be an exhaustive resource, but rather a small window into the knowledge available on the diseases we cover on our test panels. Our goal is to assist patients in learning more about these conditions in order to establish a conversation with their healthcare providers, and as such these blogs should not be taken as medical advice. Please discuss any concerns or personal risks associated with the diseases found in this series with your healthcare team.

A Genetic Deep Dive: Coronary Artery Disease (CAD)

It is widely known that heart disease is a significant global health concern, taking many lives and severely impacting many more. This is especially true of the most common type of heart disease, Coronary Artery Disease (CAD), which affects 1 in 20 adults (aged 20 and over) and claimed over 375,000 lives in 2021 according to the CDC. Though this condition has such a severe impact on both healthcare systems and quality of life globally, it is considered a highly actionable and often preventable disease. This is because research has identified both risk factors to help avoid the development of CAD, as well as technological advances and support therapies which can help lower mortality rates and offset its other serious complications. 

The heart is a very important muscle which pumps blood throughout the body–providing oxygen, nutrients, and hormones that all organs need to function properly. It manages this process with a system of arteries, which are like flexible tubes lined with muscle tissue that help them to expand and contract when needed. When these arteries get clogged, it’s called atherosclerosis. Think of it like a pipe collecting dirt over time and blocking the flow of water — but instead of dirt the body collects plaque (fats, cholesterol, calcium, and other substances) that make the artery narrower and harder, hindering blood flow. Atherosclerosis can happen anywhere in the body where arteries are found, but in the case of CAD, it occurs in the coronary arteries that supply blood directly to the heart, and there are 3 types:

• Obstructive CAD - this is when plaque buildup causes a complete or almost complete obstruction of blood flow
• Non-Obstructive CAD - this type doesn't involve plaque buildup, but occurs when other conditions damage the artery or the heart muscle causing it to narrow too much for proper blood flow
• Spontaneous Coronary Artery Dissection (SCAD) - this is when the artery wall tears suddenly, blocking blood flow

In all cases of CAD, the heart is not getting the blood that it needs, which leads to complications such as heart attack in severe cases.

Actionability Factors (why is knowing your risk important?): 

Coronary Artery Disease, when left unmonitored and uncontrolled can lead to:

• Weakening of the heart muscle, causing symptoms such as: 
  • Arrhythmia (abnormal heart rhythm)
  • Cardiogenic shock - a life-threatening condition in which the heart suddenly can't pump enough blood to meet the body's needs. This condition is often caused by heart attack, but not always
  • Heart failure - a condition where the heart can’t pump blood properly, limiting the supply to the whole body
  • Stroke - a condition caused by an interruption of blood supply to the brain, which causes parts of the brain to become damaged or die
• Complete arterial blockage, which can cause a heart attack
• Development of additional heart disease such as:
  • Carotid Artery Disease
  • Abdominal Aortic Aneurysm (AAA)
  • Peripheral Artery Disease 
• Death

Risk Factors:

Below is non-exhaustive list* of risk factors that can contribute to the development of CAD

Modifiable Risk Factors (Risks you can control)

• Personal History of:
  • High Blood Pressure (hypertension)
  • Abnormal lipid profiles (a panel of blood tests) characterized by: increased Triglyceride levels (a type of fat), increased low-density lipoprotein (LDL-C or “bad” cholesterol), and decreased high-density lipoprotein (HDL-C or “good” cholesterol)
    • It is important to note that in some cases, cholesterol issues can be inherited and difficult or impossible to control with diet and exercise alone.
  • Often preventable medical conditions such as:
    • Type 2 Diabetes
    • Chronic Kidney Disease
    • Clinically diagnosed obesity 
  • Certain lifestyle/environmental choices such as:
    • Smoking and/or exposure to secondhand smoke
    • Excessive alcohol consumption
    • A diet with excessive levels of sugar, sodium, and/or trans fats
    • Lack of physical exercise
    • Lack of restful sleep
    • Excessive levels of stress (particularly long-term)

Non-Modifiable Risk Factors (Risks outside of your control)

• Increasing age (65 or older)
• Being assigned male at birth (AMAB) or taking testosterone for hormone replacement therapy
• Personal History of:
  • Premature menopause (before age 40) and/or a history of preeclampsia during pregnancy
  • Peripheral Artery Disease
  • Depression
  • Chronic Inflammatory conditions such as: Psoriasis, HIV/AIDS, Rheumatoid Arthritis, or Lupus
• Ancestry: Those of South Asian descent are more likely to develop CAD
• Family history** of:
  • CAD in a parent or sibling: this is a strong predictor of disease
  • Premature atherosclerotic cardiovascular disease (ASCVD) before age 55 for men and 65 for women

*There are additional discussions surrounding possible risk factors for CAD, such as sleep apnea, periodontal disease, and various vitamin/protein deficiencies (among others), but research is still being conducted to clarify direct links. This blog is not intended to be an exhaustive resource for the various risks associated with CAD. Please discuss possible risks with a healthcare professional.

**It is important to note that family histories are not always reliable sources of information or risk, as not all patients can accurately describe their family history. Please see the ‘Family History’ section below for more specific information about these risks.

Family History Considerations:

hough much research has been conducted investigating the genetic underpinnings of CAD risk, there is much about its heritability that is still unknown. Despite the current gaps in understanding, however, it remains clear that one of the main risk factors for CAD is having a family history of the disease. In fact, CAD risk increases linearly (in line with) with an increase in the number of affected family members an individual has. Studies have suggested that 72% of patients with premature CAD have a family history of the disease. 

The fact that having a family history of CAD increases one’s risk for developing the disease is believed to be due to two main causes: inherited genetic variants (which we have explained in past blogs) and shared environmental & behavioral factors. For example, a family that lives in an environment without access to heart-healthy foods may not be able to develop healthy cooking and eating habits to pass down from generation to generation. Or, a family that has experienced generations of habits like smoking or a sedentary lifestyle may find it challenging to adopt new, more heart-healthy habits such as not smoking and/or exercising regularly. These types of environmental contributors to CAD risk can act alone or together with possible inherited CAD risk factors to increase an individual or family’s overall risk of developing the disease. 

Polygenic Risk Assessment (PRA) Considerations:

As discussed in previous Genomics101 blogs, a polygenic risk assessment is a numerical score that is calculated based on your personal genetic information, and it can estimate your specific genetic risk of developing certain diseases. In regards to Coronary Artery Disease, recent studies have pointed towards the utility of PRS as both an independent and collaborative source of information on disease risk. Studies have shown that its use alongside integrative methodologies (such as personal and family history assessments) and other clinical variables (such as lipid profiles, etc) can help predict future risk and improve already existing models of conventional CAD care. There are even studies that suggest PRS may be able to help clinical teams better stratify CAD risk among subjects with borderline or intermediate ASCVD risk. For more information and a link to this study, please see our blog “The Science Behind Polygenic Risk Scores - Coronary Artery Disease (CAD).” 

Other Notable Genetic Variants:

Some people may inherit certain genetic changes (variants) in single genes that result in substantially increased CAD risk. Some examples include variants in a gene called TTN, which result in very high risk for a form of heart disease called dilated cardiomyopathy, or variants in genes called LDLR, APOB, or PCSK9, which result in very high cholesterol levels. Patients found to be at high risk for CAD due to family history or personal risk factors should speak with their healthcare team about whether genetic testing for these types of genes may be appropriate for them.

Here are some things to consider when examining the prevention, symptoms, and diagnosis of Coronary Artery Disease

Prevention

• There is no way to “100% guarantee” the prevention of CAD, but the following tips are known to reduce the risk of developing it:
• Avoid smoking or exposure to secondhand smoke
• Keep metabolic and other relevant health conditions (such as diabetes, chronic kidney disease, and hypertension) under control with proper surveillance and care
• Maintain an overall healthy lifestyle via:
  • Managing weight within a healthy range for the individual
  • Maintaining a healthy diet low in salt, sugar, and trans fats
  • Regular physical activity/exercise
  • Controlling stress-levels with proper management of mental health as well as maintaining healthy sleep habits

Symptoms

• Symptoms of CAD can sometimes mimic those of other heart conditions, which means it is important to pay close attention to symptoms and follow up with a healthcare provider for proper testing and diagnosis. These symptoms may include:
  • Chest Pain and/or discomfort (collectively known as angina)
  • Nausea
  • Neck pain
  • Sleep disturbances
  • Fatigue
  • Heart attack*:
    • Angina
    • Weakness 
    • Light-headedness. Can be accompanied by cold sweat
    • Nausea
    • Pain or discomfort in arms, shoulders, back, jaw or/and upper stomach
    • Shortness of breath or trouble breathing
    • Fatigue, i.e feeling very, very tired (more than what is normal for you)

*It is worth noting that for those assigned female at birth (AFAB), symptoms of heart attack may not be very straightforward (such as presenting with severe chest pain). AFAB individuals are more likely to notice the more subtle symptoms of heart attack such as: extreme tiredness, nausea, pressure or tightness in the chest, dizziness and/or stomach pain. 

Diagnosis

The diagnostic process for CAD may include:

• Electrocardiogram - This test measures the electrical activity of the heart and helps provide an understanding of the heart’s pace and rhythm. 
• Echocardiogram - This test looks at the blood flow within the heart to determine if it is abnormal or insufficient.
• Exercise stress test - This test examines how the heart reacts to the strain of exercise and  involves performing activities such as walking or utilizing a stationary bike while a team measures the heart’s response. For individuals unable to exercise, the strain is often simulated via a medication instead. 
• Nuclear stress test - This test is very similar to the exercise stress test, however it adds imaging such as electrocardiogram, which allows the medical team to visualize how blood flows to the heart in both rest and stress conditions in real time. This is done utilizing a radioactive ‘tracer,’ which is administered intravenously (directly into the veins) and ‘flows’ through the bloodstream during the testing process.
• Chest x-ray - This is a non-invasive method which produces an image of the lungs and heart
• Cardiac catheterization - This test is widely used by doctors for heart or blood vessel specific problems, by using a catheter (thin flexible tube) inserted directly into the blood vessels, and checks for the hallmark characteristics of CAD such as plaque buildup, abnormal blood flow, and narrowing of the blood vessel.
• Coronary angiogram/CT (Computed Tomography) angiogram - This test uses a machine to scan the arteries and how well they supply blood to the heart.
• Coronary artery calcium scan - This is another type of CT that scans the heart looking specifically for calcium buildup

Living with CAD:

The primary goal of all Coronary Artery Disease management techniques are to prevent or lessen further damage and/or narrowing of the coronary arteries. The overall approach to CAD management typically includes proper surveillance and medical treatment, as well as assisting patients with maintaining specific lifestyle changes that increase heart health. These lifestyle changes include many of the notes in the ‘prevention’ section of this blog, such as following a healthy diet (paying special attention to cholesterol, triglycerides and trans-fats), taking part in regular physical activity or exercise, avoiding smoking or second hand smoke exposure, and managing blood pressure. 

Studies have shown that quitting smoking can reduce the risk of heart attack by up to 50% for those that have already experienced a prior attack. This highlights the incredible impact that certain lifestyle choices can have on maintaining a high quality of life with CAD. This does not mean that all cases of CAD can be managed by modifying lifestyle choices alone, and it is not uncommon for people to need medical procedures such as angioplasty or coronary artery bypass graft surgery in order to restore their lost blood flow. It’s important to note that the symptoms and severity of CAD will vary from person to person, and any treatment course should happen under the watchful eye of a healthcare professional. 

Common Medications:

There are a variety of medications available for CAD treatment which are used to treat different specific symptoms of the disease. For example, some of these medications seek to prevent angina (chest pain) or other symptoms that decrease quality of life, while some work to actively prevent or reverse the narrowing of arteries themselves. It is important to note that these medications should be administered under the watchful eye of a healthcare professional, and are often recommended on a case by case basis depending on the severity of the disease for the individual. Some examples of CAD medications often include: 

• Nitrates - These medications lower blood pressure, thereby reducing strain on the heart, often relieving pain associated with CAD.
• Morphine - This is a pain-relieving and calming medication which can reduce the heart’s workload and also reduce heart-attack related anxiety.
• Beta-Blockers - These medications slow the heart rate, allowing the heart to work less which can decrease the amount of damage being done to arterial tissue.
• Calcium channel blockers - These medications can reduce blood pressure, which helps prevent arteries from further narrowing. They are often used as a substitute for beta-blockers.
• Ranolazine - This medication helps reduce angina for patients struggling with chest pain symptoms. It is commonly prescribed alongside or in replacement of beta-blockers.
• ACE inhibitors and angiotensin II receptor blockers - These medications reduce enlargement of the heart, and are often administered as a method to avoid heart attack.
• Statins - These medications help by blocking a liver enzyme that creates cholesterol, thereby reducing cholesterol levels in the blood. 
• Antiplatelet drugs (including aspirin) - Many CAD patients are prescribed a low-dose aspirin to take as a daily preventative medication. This helps prevent heart attacks because aspirin can thin blood so that it is less likely to ‘clump’. Other antiplatelet drugs include ticlopidine, clopidogrel or intravenously administered glycoprotein inhibitors.
• Nitroglycerin - this medicine widens the arteries, which can relieve chest pain as blood is able to flow more easily to the heart.
• Anticoagulants - This medication can help prevent blood clots from forming by making blood less likely to ‘clump’. A common example of this type of medication is heparin.

Technology and CAD Management

Technology surrounding management of CAD often emphasizes the prevention of symptoms by monitoring lifestyle choices rather than directly treating the disease, as patient adherence to lifestyle recommendations can often be challenging. In recent years, telehealth technology has emerged as a popular solution, enabling easier and more streamlined communication with healthcare professionals from the comfort of a patient’s home. Examples of telehealth interventions include text message support, telephone calls, and telemonitoring (which, again, typically targets risk factors rather than physical symptoms themselves). Research has shown positive outcomes in metrics like waist circumference, blood pressure, total cholesterol, triglycerides, medication adherence, physical activity, and smoking cessation as a result of these telehealth interventions. Other technological advances explore the use of smartphones, wristbands, scales, and blood pressure monitors to enhance at-home CAD management. This approach focuses on long-term consistency in lifestyle choices, recognizing that CAD may take years to significantly progress, with symptoms sometimes developing only directly before a major event such as a heart attack.

Resources for living with CAD:

• Support Groups:
  • https://www.heart.org/ 
    • The American Heart Association serves as a resource for overall cardiovascular health, offering a wealth of information, educational materials, and access to additional support networks that empower individuals to prevent and manage heart-related issues.
  • https://www.womenheart.org
    • WomenHeart is a comprehensive support resource providing education, advocacy, and community for women living with or at risk of heart disease
• Articles on supporting loved ones with CAD:
  • Kaiser Permanente Article: Coronary Artery Disease: Helping a Loved One. 

• It is estimated that 1 in 20 adults 20 years of age and older are currently living with CAD
• CAD represents about 2.2% of the overall global burden of disease 
• CAD specifically accounts for more than 32% of all cardiovascular diseases 

Coronary Artery Disease is a common but significant medical condition that affects millions of people worldwide. Despite its prevalence it is incredibly actionable, with many preventative measures able to be taken under the guidance of a healthcare team to avoid development or progression of the disease for those with modifiable risk factors. New methods of prevention, monitoring, and treatment are constantly being developed via careful research to minimize the negative impacts CAD can have on quality of life for those suffering with this condition.

• Arteries - flexible tube-like structures in the body that help move blood and nutrients throughout the body’s systems. They are lined with muscle tissue that help them to expand and contract when needed. 
• Atherosclerosis - this occurs when arteries in the body are blocked in some way, reducing blood flow
• Arrhythmia - an abnormal heart rhythm
• Chronic total occlusion:  When one or more of the coronary arteries become completely (or nearly completely) blocked.
• Plaque - fats, cholesterol, calcium, and other substances which can collect in arteries, blocking blood flow
• GWAS - Genome-wide association study. This is a widely used research approach which identifies genetic variants that are associated with a risk for disease.
• Blood Pressure Monitor - a device which measures pressure in the arteries as the heart pumps blood.

• Websites:
  • CDC: (1, 2, 3, 4, 5)
  • Mayo Clinic (1, 2)
  • Cleveland Clinic (1)
  • Pennmedicine.org (1, 2)
  • John Hopkins Medicine (1)
  • Mount Sinai (1)
  • HeartandStroke.ca (1)
  • NIH (1, 2, 3, 4)
  • NYU Langone Health (1)
  • Nature.com (1)

• Journal Articles:
  • Risk Factors for Coronary Artery Disease, PMID: 32119297 (1)
  • Genetics of Coronary Artery Disease (1)
  • Systems Genetics Analysis of Genome-Wide Association Study Reveals Novel Associations Between Key Biological Processes and Coronary Artery Disease (1)
  • Gene–environment interaction in dyslipidemia (1)
  • Pathophysiology of Cardiovascular Diseases: New Insights into Molecular Mechanisms of Atherosclerosis, Arterial Hypertension, and Coronary Artery Disease (1)
  • Family history of cardiovascular disease and risk of premature coronary heart disease: A matched case-control study. PMID: 32518841 (1)
  • Genetics of coronary artery disease: discovery, biology and clinical translation. PMID: 28286336 (1)
  • A multi-ancestry polygenic risk score improves risk prediction for coronary artery disease. (1)
  • Family history of cardiovascular disease and risk of premature coronary heart disease: A matched case-control study. PMID: 32518841. (1)
  • Reclassification of coronary artery disease risk using genetic risk score among subjects with borderline or intermediate clinical risk. PMID: 36275420. (1)
  • Predictive Utility of a Coronary Artery Disease Polygenic Risk Score in Primary Prevention (1)
  • Clinical Implementation of Combined Monogenic and Polygenic Risk Disclosure for Coronary Artery Disease (1)
  • Digital health technology in the prevention of heart failure and coronary artery disease. PMID: 36589760. (1)
  • The Effects of Mobile Health Care on the Physiological Index in Patients With Coronary Artery Disease. PMID: 31960398 (1)
  • Effectiveness of telehealth interventions as a part of secondary prevention in coronary artery disease: a systematic review and meta-analysis (1)
  • An Overview of Telehealth in the Management of Cardiovascular Disease: A Scientific Statement From the American Heart Association (1)