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17.7: Cardiovascular Disease - Biology


Heart Attack on a Plate

Eating this greasy cheeseburger smothered in bacon may not literally cause a heart attack. However, regularly eating high-fat, low-fiber foods such as this may increase the risk of a heart attack or other type of cardiovascular disease. In fact, unhealthy lifestyle choices such as this may account for as many as 90 percent of cases of cardiovascular disease.

What Is Cardiovascular Disease?

Cardiovascular disease is a class of diseases that involve the cardiovascular system. They include diseases of the coronary arteries that supply the heart muscle with oxygen and nutrients; diseases of arteries such as the carotid artery that provide blood flow to the brain; and diseases of the peripheral arteries that carry blood throughout the body. Worldwide, cardiovascular disease is the leading cause of death, causing about a third of all deaths each year.

Most cases of the cardiovascular disease occur in people over the age of 60, with disease onset typically being about a decade earlier in males than females. The LGBT (lesbian, gay, bisexual, and transgender) community belongs to almost every race, ethnicity, religion, age, and socioeconomic group. The LGBT youth are at a higher risk for cardiovascular diseases, obesity, anxiety, and depression as compared to the general population. LGBT youth receive poor quality of care due to stigma, lack of healthcare providers’ awareness, and insensitivity to the unique needs of this community. Young LGBT individuals find it difficult to report their sexual identity to their clinicians. Some clinicians are not well trained in addressing the concerns of members of this community.

You can’t control your age or sex, but you can control other factors that increase the risk of cardiovascular disease. Not smoking, maintaining a healthy weight, eating a healthy diet, taking medications as needed to control diabetes and cholesterol, and getting regular exercise are all ways to prevent cardiovascular disease or keep it from progressing. It should be noted that high blood lipid levels are definitely risk factors for cardiovascular disease. High levels of cholesterol in the diet do not appear to lead directly to high levels of cholesterol in the blood. Clearly, cardiovascular disease is multifactorial in terms of its causes.

Precursors of Cardiovascular Disease

There are two very common conditions that are precursors to virtually all cases of cardiovascular disease: hypertension (hypertension) and atherosclerosis (hardening of blood wall). Both conditions affect the arteries and their ability to maintain normal blood flow.

Hypertension

Hypertension is a chronic medical condition in which the blood pressure in the arteries is persistently elevated, as defined in Table (PageIndex{1}). Hypertension usually does not cause symptoms, so more than half of the people with high blood pressure are unaware of their condition. Hypertension is typically diagnosed when blood pressure is routinely measured during a medical visit for some other health problem.

Table (PageIndex{1}): Classification of Blood Pressure (in Adults)

Category

Systolic (mm Hg)

Diastolic (mm Hg)

Normal blood pressure

90-119

60-79

Prehypertension

120-139

80-89

Hypertension

140 or higher

90 or higher

High blood pressure is classified as either primary or secondary high blood pressure. At least 90% of cases are primary high blood pressure, which is caused by some combination of genetic and lifestyle factors. Numerous genes have been identified as having small effects on blood pressure. Lifestyle factors that increase the risk of high blood pressure include excess dietary salt and alcohol consumption in addition to the risk factors for cardiovascular disease stated above. Secondary high blood pressure, which makes up the remaining 10% of cases of hypertension, is attributable to chronic kidney disease or an endocrine disorder such as Cushing’s disease.

Treating hypertension is important for reducing the risk of all types of cardiovascular disease, especially stroke. These and other complications of persistent high blood pressure are shown in Figure (PageIndex{2}). Lifestyle changes, such as reducing salt intake and adopting a healthier diet may be all that is needed to lower blood pressure to the normal range. In many cases, however, medications are also required.

Atherosclerosis

Atherosclerosis is a condition in which artery walls thicken and stiffen as a result of the buildup of plaques inside the arteries. Plaques consist of white blood cells, cholesterol, and other fats. Typically, there is also a proliferation of smooth muscle cells that make the plaque fibrous as well as fatty. Over time, the plaques may harden with the addition of calcium crystals. This reduces the elasticity of the artery walls. As plaques increase in size, the artery walls dilate to compensate so blood flow is not affected. Eventually, however, the lumen of the arteries is likely to become so narrowed by plaque buildup that blood flow is reduced or even blocked entirely. Figure (PageIndex{3}) illustrates the formation of a plaque in a coronary artery.

In most people, plaques start to form in arteries during childhood and progress throughout life. Individuals may develop just a few plaques or dozens of them. Plaques typically remain asymptomatic for decades. Signs and symptoms appear only after there is severe narrowing (stenosis) or complete blockage of arteries. As plaques increase in size and interfere with blood flow, they commonly lead to the formation of blood clots. These may plug arteries at the site of the plaque or travel elsewhere in the circulation. Sometimes plaques rupture or become detached from an arterial wall and become lodged in a smaller, downstream artery. Blockage of arteries by plaques or clots may cause a heart attack, stroke, or other potentially life-threatening cardiovascular events. If blood flow to the kidneys is affected, it may lead to chronic kidney disease.

The process in which plaques form is not yet fully understood, but it is thought that it begins when low-density lipoproteins (LDLs) accumulate inside endothelial cells in artery walls, causing inflammation. The inflammation attracts white blood cells that start to form a plaque. Continued inflammation and a cascade of other immune responses cause the plaque to keep growing. Risk factors for the development of atherosclerosis include hypertension, high cholesterol (especially LDL cholesterol), diabetes, and smoking. The chance of developing atherosclerosis also increases with age, male sex, and a family history of cardiovascular disease.

Treatment of atherosclerosis often includes both lifestyle changes and medications to lower cholesterol, control blood pressure, and reduce the risk of blood clot formation. In extreme cases or when other treatments are inadequate, surgery may be recommended. Surgery may involve the placement of stents in arteries to keep them open and improve blood flow or the use of grafts to divert blood flow around blocked arteries.

Coronary Artery Disease

Coronary artery diseases are a group of diseases that result from atherosclerosis of coronary arteries. Treatment of the diseases mainly involves treating underlying atherosclerosis. Two of the most common coronary artery diseases are angina and myocardial infarction.

Angina

Angina is chest pain or pressure that occurs when heart muscle cells do not receive adequate blood flow and become starved of oxygen (a condition called ischemia). It is illustrated in Figure (PageIndex{4}). There may also be a pain in the back, neck, shoulders, or jaw; and in some cases, the pain may be accompanied by shortness of breath, sweating, or nausea. The main goals of the treatment of angina are relieving the symptoms and slowing the progression of underlying atherosclerosis.

Angina may be classified as either stable angina or unstable angina:

  • Stable angina is angina in which pain is precipitated by exertion (say, from brisk walking or running) and improves quickly with rest or the administration of nitroglycerin, which dilates coronary arteries and improves blood flow. Stable angina may develop into unstable angina.
  • Unstable angina is angina in which pain occurs during rest, lasts more than 15 minutes, and is of new onset. This type of angina is more dangerous and may be a sign of an imminent heart attack. It requires urgent medical attention.

Myocardial Infarction

A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow stops to a part of the heart causing damage to the heart muscle and the death of myocardial cells. An MI usually occurs because of complete blockage of a coronary artery, often due to a blood clot or the rupture of a plaque (Figure (PageIndex{5})). An MI typically causes chest pain and pressure, among other possible symptoms, but at least one-quarter of MIs do not cause any symptoms.

In the worst case, an MI may cause sudden death. Even if the patient survives, an MI often causes permanent damage to the heart. This puts the heart at risk of heart arrhythmias, heart failure, and cardiac arrest.

  • Heart arrhythmias are abnormal heart rhythms, which are potentially life-threatening. Heart arrhythmias often can be interrupted with a cardiac defibrillator, which delivers an electrical shock to the heart, in effect “rebooting” it.
  • Heart failure occurs when the pumping action of the heart is impaired so tissues do not get adequate oxygen. This is a chronic condition that tends to get worse over time, although it can be managed with medications.
  • Cardiac arrest occurs when the heart no longer pumps blood or pumps blood so poorly that vital organs can no longer function. This is a medical emergency requiring immediate intervention.

Other Cardiovascular Diseases

Hypertension and atherosclerosis often cause other cardiovascular diseases. These commonly include stroke and peripheral artery disease.

Stroke

A stroke, also known as a cerebrovascular accident or brain attack, occurs when blocked or broken arteries in the brain result in the death of brain cells. There are two main types of stroke: ischemic stroke and hemorrhagic stroke. Ischemic storke is illustrated in Figure (PageIndex{6}).

  1. An ischemic stroke occurs when an embolus (blood clot) breaks off from a plaque or forms in the heart because of arrhythmia and travels to the brain where it becomes lodged in an artery. This blocks blood flow to the part of the brain that is served by arteries downstream from the blockage. Lack of oxygen causes the death of brain cells. Treatment with a clot-busting drug within a few hours of the stroke may prevent permanent damage. Almost 90 percent of strokes are ischemic strokes.
  2. A hemorrhagic stroke occurs when an artery in the brain ruptures and causes bleeding in the brain. This deprives downstream tissues of adequate blood flow and also puts pressure on brain tissue. Both factors can lead to the death of brain cells. Surgery to temporarily open the cranium may be required to relieve the pressure. Only about 10 percent of strokes are hemorrhagic strokes, but they are more likely to be fatal than ischemic strokes.

In both types of stroke, the part of the brain that is damaged loses is the ability to function normally. Signs and symptoms of stroke may include an inability to move, feel, or see on one side of the body; problems understanding speech or difficulty speaking; memory problems; confusion; and dizziness. Hemorrhagic strokes may also cause a severe headache. The symptoms of a stroke usually occur within seconds or minutes of the brain injury. Depending on the severity of the stroke and how quickly treatment is provided, the symptoms may be temporary or permanent. If the symptoms of a stroke go away on their own in less than an hour or two, the stroke is called a transient ischemic attack. Stroke is the leading cause of disability in the United States, but rehabilitation with physical, occupational, speech, or other types of therapy may significantly improve functioning.

The main risk factor for stroke is high blood pressure. Therefore, keeping blood pressure within the normal range, whether with lifestyle changes or medications, is the best way to reduce the risk of stroke. Another possible cause of stroke is the use of illicit drugs such as amphetamines or cocaine. Having had a stroke in the past greatly increases one’s risk of future strokes. Men are also more likely than women to have strokes.

Peripheral Artery Disease

Peripheral artery disease (PAD) is the narrowing of the arteries other than those that supply the heart or brain due to atherosclerosis. Figure (PageIndex{7}) shows how the PAD occurs. PAD most commonly affects the legs, but other arteries may also be involved. The classic symptom is leg pain when walking, which usually resolves with rest. This symptom is known as intermittent claudication. Other symptoms may include skin ulcers, bluish skin, cold skin, or poor nail and hair growth in the affected leg(s). However, up to half of all cases of PAD do not have any symptoms.

The main risk factor for PAD is smoking. Other risk factors include diabetes, high blood pressure, and high blood cholesterol. The underlying mechanism is usually atherosclerosis. PAD is typically diagnosed when blood pressure readings taken at the ankle are lower than blood pressure readings taken at the upper arm. It is important to diagnose PAD and treat underlying atherosclerosis because people with this disorder have a four to five times higher risk of myocardial infarction or stroke. Surgery to expand the affected arteries or to graft vessels in order to bypass blockages may be recommended in some cases.

Feature: My Human Body

You read in this concept about the many dangers of hypertension. Do you know whether you have hypertension? The only way to know for sure is to have your blood pressure measured. Measuring blood pressure is quick and painless, but several measurements are needed to accurately diagnose hypertension. Some people have what is called “white coat disease.” Their blood pressure rises just because they are being examined by a physician (in a white coat). Blood pressure also fluctuates from time to time due to factors such as hydration, stress, and time of day. Repeatedly measuring and recording your own blood pressure at home can provide your doctor with valuable diagnostic data. Digital blood pressure monitors for home use, like the one pictured in Figure (PageIndex{8}), are relatively inexpensive, easy to use, and available at most pharmacies.

Review

  1. What is cardiovascular disease? How much mortality do cardiovascular diseases cause?
  2. List risk factors for cardiovascular disease.
  3. What is hypertension?
  4. Define atherosclerosis.
  5. What is coronary artery disease?
  6. Identify two specific coronary artery diseases.
  7. Explain how a stroke occurs and how it affects the patient.
  8. Describe the cause of peripheral artery disease.
  9. What are two cardiovascular diseases that can be caused by atherosclerosis? Explain specifically how atherosclerosis contributes to each of them.
  10. True or False. A heart attack is the same thing as cardiac arrest.
  11. True or False. Plaques in arteries can cause blood clots.
  12. What are the similarities between angina and ischemic stroke?
  13. How can kidney disease be caused by problems in the cardiovascular system?
  14. In peripheral artery disease, the blood pressure at the ankle is typically ________ the blood pressure at the upper arm.

    A. erratic compared to B. the same as

    C. higher than D. lower than

  15. Name three components of the plaque that can build up in arteries.

Attributions

  1. Bacon Cheeseburger by Like_the_Grand_Canyon licensed CC-BY 2.0 via Wikimedia Commons
  2. Main complications of persistent high blood pressure Häggström, Mikael (2014). "Medical gallery of Mikael Häggström 2014". WikiJournal of Medicine 1 (2). DOI:10.15347/wjm/2014.008. ISSN 2002-4436. Public Domain. via Wikimedia Commons
  3. Coronary heart disease-atherosclerosis by NIH: National Heart, Lung and Blood Institute. Public Domain.
  4. Angina by Blausen.com staff (2014). "Medical gallery of Blausen Medical 2014". DOI:10.15347/wjm/2014.010. ISSN 2002-4436. licensed CC BY 3.0 via Wikimedia Commons.
  5. Heart Attack by NIH: National Heart, Lung and Blood Institute; public domain via Wikimedia Commons.
  6. Stroke Ischemic by National Heart Lung and Blood Insitute (NIH); Public domain via Wikimedia Commons
  7. Peripheral Arterial Disease by National Heart Lung and Blood Institute; public domain via Wikimedia Commons
  8. Wrist style blood pressure monitor by Weeksgo licensed https://creativecommons.org/publicdomain/zero/1.0/deed.enCC0 via Wikimedia commons.
  9. Text adapted from Human Biology by CK-12 licensed CC BY-NC 3.0
  10. Some text is adapted from Health Care Disparities Among Lesbian, Gay, Bisexual, and Transgender Youth: A Literature Review; Hudaisa Hafeez, Muhammad Zeshan, Muhammad A Tahir, Nusrat Jahan, and Sadiq Naveed; Cureus. 2017 Apr; 9(4): e1184. Published online 2017 Apr 20. doi: 10.7759/cureus.1184; CC By 4.0.

Sleep, heart disease link leads from brain to bone marrow

Four years ago, Cameron McAlpine (from left) and Filip Swirski began experiments with their colleagues at MGH designed to explore the connection between poor sleep and heart disease. Credit: Jon Chase/Harvard Staff Photographer

Researchers have known for some time that poor sleep raises heart disease risk. Now, they've found a chemical chain reaction that helps explain that risk, leading from poor sleep to a white blood cell surge that promotes the artery-clogging plaques of cardiovascular disease.

The world's top killer, cardiovascular disease kills 17.7 million worldwide annually, according to figures from the World Health Organization. It has been linked to a number of risk factors, including smoking, a poor diet, and lack of exercise. A less widely known risk is chronically poor sleep, whether short or fragmented, like that experienced by night-shift workers, travelers in the grip of jet lag, and sufferers of sleep apnea and similar conditions.

"There are studies that suggest [sleep] can be as potent a driver of the disease as more traditional risk factors, such as smoking or high cholesterol levels," said Cameron McAlpine, a research fellow in the lab of Filip Swirski, an associate professor of radiology at Harvard Medical School and a researcher at Massachusetts General Hospital's Center for Systems Biology.

Four years ago, McAlpine, Swirski, and their colleagues began experiments designed to explore the connection between sleep and the immune and inflammatory mechanisms that play a role in atherosclerosis.

Atherosclerosis, also known as hardening of the arteries, is a key feature of heart disease and has come to be understood as largely an inflammatory condition, McAlpine said. It typically advances with age as fatty plaques deposit along the walls of blood vessels, narrowing them and interfering with blood flow. The atherosclerotic plaques are made up of fats like LDL, or "bad," cholesterol and white blood cells that flood to the scene and become entangled in fibers that hold the plaque together. The plaques not only reduce blood flow, they also can rupture and cause blood clots that clog arteries leading to the brain, causing strokes, or the heart, causing heart attacks.

"The research showing a link between sleep and cardiovascular disease in humans is abundant," Swirski said. "We wanted to know the 'how.' In this study we uncovered one small piece of what is surely a much larger puzzle."

Through multiple experiments, researchers found that poor sleep causes production of a protein called hypocretin to fall in the brain's hypothalamus region, which is responsible for wakefulness, energy levels, and sleep patterns. Low hypocretin levels stimulate the bone marrow to increase production of a second protein, called colony-stimulating factor 1 (CSF-1). CSF-1, in turn, signals the bone marrow's blood stem cells to step up production of white blood cells, boosting the immune and inflammatory response that is a feature of the condition.

In their experiments, conducted on mice fed a high-fat diet and genetically preprogrammed to develop atherosclerosis, the sleep-deprived mice had more white blood cells in their bloodstreams and developed larger plaques, and those plaques contained more white blood cells than those of control mice whose sleep wasn't disrupted. Researchers then gave supplemental hypocretin to the sleep-deprived mice and found that the prevalence of atherosclerosis declined.

"The role of hypocretin was certainly very, very shocking and unexpected to us. We really didn't know what to make of it initially," McAlpine said. "We had no idea we would find increasing white blood cells and this production could actually be regulated by sleep."

The research, published in February in the journal Nature, was conducted with colleagues from Brigham and Women's Hospital, Beth Israel Deaconess Medical Center, the Medical University of Vienna, and the University of Lausanne, Switzerland. It was funded by several sources, including the National Institutes of Health and the American Heart Association.

Because these results were found in laboratory mice, Swirski said the next step is to search for a similar response in people. Ultimately, he and McAlpine said, the findings highlight the importance of good sleep hygiene, while the enhanced understanding of inflammatory mechanisms could provide new avenues of investigation for other conditions in which inflammation plays a role.

"If these pathways are relevant in humans, and there is reason to suspect they are, then they may be very important for possible targeting of inflammation, perhaps beyond cardiovascular disease," Swirski said. "These pathways may be relevant in cancer, infectious disease, and many other conditions where inflammatory cells play a major role."


Cardiovascular disease burden, deaths are rising around the world

The number of people dying from cardiovascular disease (CVD) is steadily rising, including one-third of all deaths globally in 2019, according to a paper in the Journal of the American College of Cardiology that reviewed the total magnitude of CVD burden and trends over 30 years around the world. The data reflects an urgent need for countries to establish cost-effective public health programs aimed at reducing cardiovascular risk through modifiable behaviors.

CVD, particularly ischemic heart disease and stroke, is the leading cause of death around the world and a huge contributor to disability and rising health care costs. The Global Burden of Diseases, Injuries, and Risk Factors Study 2019, from which this paper uses data, is a multinational collaboration that estimates global, regional and national disease burden as part of an ongoing effort to provide consistent and comparable estimates of health from 1990-2019. It uses all available population-level data sources on incidence, prevalence, case fatality, mortality and health risks to estimate measures of population health for 204 countries and territories.

In this paper, authors look at the specific impact of cardiovascular disease within the Global Burden of Diseases study to examine the extent to which population growth and aging and CVD risk factors explain the observed CVD trends, sex differences and regional patterns, as well as how the epidemiology of the disease is evolving.

"Global patterns of total CVD have significant implications for clinical practice and public health policy development," said Gregory A. Roth, MD, MPH, lead author of the paper and associate professor in the division of cardiology and adjunct associate professor at the Institute for Health Metrics and Evaluation at the University of Washington School of Medicine. "Prevalent cases of total CVD are likely to increase substantially as a result of population growth and aging, especially in Northern Africa and Western Asia, Central and Southern Asia, Latin America and the Caribbean, and Eastern and Southeastern Asia where the share of older persons is projected to double between 2019 and 2050. Increased attention to promoting ideal cardiovascular health and healthy aging across the lifespan is necessary. Equally important, the time has come to implement feasible and affordable strategies for the prevention and control of CVD and to monitor results."

The paper includes 13 underlying causes of cardiovascular death and nine related risk factors. For each cause and risk factor, the authors identified which regions and countries have the highest and lowest prevalent cases and number of deaths, as well as summary measures including number of years of life lost (YLLs), number of years lived with disability (YLDs) and the amount and temporal trends in disability-adjusted life years (DALYs). The paper also addresses how the summary measures of each CVD and risk highlighted inform investments in cardiovascular research, their implications for clinical practice, and suggestions for health system development and national and regional policy.

Findings highlighted in the paper showed the prevalent cases of total CVD nearly doubled from 271 million in 1990 to 523 million in 2019, while the number of CVD deaths steadily increased from 12.1 million in 1990 to 18.6 million in 2019. In 2019, the majority of CVD deaths globally were ischemic heart disease and stroke, increasingly steadily from 1990. The global trends for DALYs and YLLs also increased significantly while YLDs doubled from 17.7 in 1990 to 34.4 million in 2019.

In 2019, CVD was the underlying cause of 9.6 million deaths among men and 8.9 million deaths among women, around a third of all deaths globally. Over 6 million of these deaths occurred in people between the ages of 30-70. The highest number of CVD deaths occurred in China, followed by India, Russia, the US and Indonesia.

At the country level, age-standardized mortality rates for total CVD were lowest in France, Peru and Japan where rates were six-fold lower in 2019 than in 1990. The authors of the paper note that from 1990 to 2019, large declines in the age-standardized rates of death, DALYs and YLLs together with small incremental reductions in age-standardized rates for prevalent cases, and YLDs suggest that population growth and aging are big contributors to the increase in total CVD.

The paper also discusses challenges in prevention and treatment of CVD and risks globally.

"There remains a large gap between what we know about CVD and risk factors and what we do in their prevention, treatment and control worldwide," said George A. Mensah, MD, co-lead author of the paper and director of the Center for Translation Research and Implementation Science at the National Heart, Lung, and Blood Institute, part of the National Institutes of Health. "The Global Burden of Diseases study continues to be a platform that allows tracking and benchmarking of progress in the reduction of CVD and risk factor burden. However, renewed focus is needed now on affordable, widely available and proven-effective implementation strategies for the prevention, treatment and control of CVD and risk factors and the promotion of ideal cardiovascular health beginning in childhood."

Amid the current COVID-19 pandemic, there exists high rates of excess mortality and according to the paper, much of this additional disease burden may be CVD because of the effects of both viral infection and changes in the delivery of health care and health-seeking behaviors due to pandemic mitigation efforts. However, further research in this area is vitally needed.

"There is a pressing need to focus on implementing existing cost-effective interventions and health policies if the world is to meet the targets for Sustainable Development Goal 3 and achieve at least a 30% reduction in premature mortality due to non-communicable disease by 2030," said Valentin Fuster, MD, PhD, senior author of the paper, Director of Mount Sinai Heart and Physician-in-Chief of The Mount Sinai Hospital. "In the face of a global viral pandemic, we still must emphasize global commitments to reduce the suffering and premature death caused by CVD, which limits healthy and sustainable development for every country in the world."

The American College of Cardiology envisions a world where innovation and knowledge optimize cardiovascular care and outcomes. As the professional home for the entire cardiovascular care team, the mission of the College and its 54,000 members is to transform cardiovascular care and to improve heart health. The ACC bestows credentials upon cardiovascular professionals who meet stringent qualifications and leads in the formation of health policy, standards and guidelines. The College also provides professional medical education, disseminates cardiovascular research through its world-renowned JACC Journals, operates national registries to measure and improve care, and offers cardiovascular accreditation to hospitals and institutions. For more, visit acc.org.

The Journal of the American College of Cardiology ranks among the top cardiovascular journals in the world for its scientific impact. JACC is the flagship for a family of journals--JACC: Cardiovascular Interventions, JACC: Cardiovascular Imaging, JACC: Heart Failure, JACC: Clinical Electrophysiology, JACC: Basic to Translational Science, JACC: Case Reports and JACC: CardioOncology--that prides themselves in publishing the top peer-reviewed research on all aspects of cardiovascular disease. Learn more at JACC.org.

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.


Instant death from heart attack more common in people who do not exercise

Sophia Antipolis, 12 February 2021: An active lifestyle is linked with a lower chance of dying immediately from a heart attack, according to a study published today in the European Journal of Preventive Cardiology, a journal of the European Society of Cardiology (ESC). 1

Heart disease is the leading cause of death globally and prevention is a major public health priority. The beneficial impact of physical activity in stopping heart disease and sudden death on a population level is well documented. This study focused on the effect of an active versus sedentary lifestyle on the immediate course of a heart attack &ndash an area with little information.

The researchers used data from 10 European observational cohorts including healthy participants with a baseline assessment of physical activity who had a heart attack during follow-up &ndash a total of 28,140 individuals. Participants were categorised according to their weekly level of leisure-time physical activity as sedentary, low, moderate, or high.

The association between activity level and the risk of death due to a heart attack (instantly and within 28 days) was analysed in each cohort separately and then the results were pooled. The analyses were adjusted for age, sex, diabetes, blood pressure, family history of heart disease, smoking, body mass index, blood cholesterol, alcohol consumption, and socioeconomic status.

A total of 4,976 (17.7%) participants died within 28 days of their heart attack &ndash of these, 3,101 (62.3%) died instantly. Overall, a higher level of physical activity was associated with a lower risk of instant and 28-day fatal heart attack, seemingly in a dose&ndashresponse-like manner. Patients who had engaged in moderate and high levels of leisure-time physical activity had a 33% and 45% lower risk of instant death compared to sedentary individuals. At 28 days these numbers were 36% and 28%, respectively. The relationship with low activity did not reach statistical significance.

Study author Dr. Kim Wadt Hansen of Bispebjerg Hospital, Copenhagen, Denmark said: &ldquoAlmost 18% of patients with a heart attack died within 28 days, substantiating the severity of this condition. We found an immediate survival benefit of prior physical activity in the setting of a heart attack, a benefit which seemed preserved at 28 days.&rdquo

He noted: &ldquoBased on our analyses, even a low amount of leisure-time physical activity may in fact be beneficial against fatal heart attacks, but statistical uncertainty precludes us from drawing any firm conclusions on that point.&rdquo

The authors said in the paper: &ldquoOur pooled analysis provides strong support for the recommendations on weekly physical activity in healthy adults stated in the 2016 European Guidelines on cardiovascular disease prevention in clinical practice 2 especially as we used cut-off values for physical activity comparable to those used in the guidelines.&rdquo

The guidelines recommend that healthy adults of all ages perform at least 150 minutes a week of moderate intensity or 75 minutes a week of vigorous intensity aerobic physical activity or an equivalent combination thereof.

Dr. Hansen concluded: &ldquoThere are many ways to be physically active at little or no cost. Our study provides yet more evidence for the rewards of exercise.&rdquo

Notes to editor

ESC Press Office
Tel: +33 (0) 7 8531 2036
Email: [email protected]

Funding: The Danish Heart Foundation (18-R124-A8318-22104). The funding source was not involved in study design collection, analysis, and interpretation of data writing of the report or the decision to submit the report for publication.

Disclosures: none declared.

1 Hansen KW, Peytz N, Blokstra A, et al. Association of fatal myocardial infarction with past level of physical activity: a pooled analysis of cohort studies. Eur J Prev Cardiol. 2021. doi:10.1093/eurjpc/zwaa146.

Link will go live on publication:

2 Piepoli MF, Hoes AW, Agewall S, et al. 2016 European Guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J. 201637:2315&ndash2381.

The ESC brings together health care professionals from more than 150 countries, working to advance cardiovascular medicine and help people to live longer, healthier lives.

About the European Journal of Preventive Cardiology
The European Journal of Preventive Cardiology is the world's leading preventive cardiology journal, playing a pivotal role in reducing the global burden of cardiovascular disease.


A CRISPR edit for heart disease

Anthony King is a freelance science writer based in Dublin.

You can also search for this author in PubMed Google Scholar

Kiran Musunuru (centre) and his team are using genome editing in the mouse liver to modify enzymes that regulate levels of ‘bad’ cholesterol. Credit: Peggy Peterson Photography

Consider this scenario: it’s 2037, and a middle-aged person can walk into a health centre to get a vaccination against cardiovascular disease. The injection targets cells in the liver, tweaking a gene that is involved in regulating cholesterol in the blood. The simple procedure trims cholesterol levels and dramatically reduces the person’s risk of a heart attack.

According to World Health Organization statistics published in 2015, ischaemic heart disease and stroke are the leading causes of death worldwide. About 17.7 million people died from cardiovascular disease that year, and at least three-quarters of those deaths occurred in low- and middle-income countries. Although antibody-based therapies have been launched to help those most at risk, the cost and complexity of the treatments means that a simpler, one-off fix such as a vaccine would be of benefit to many more people around the world.

Part of Nature Outlook: The future of medicine

The good news is that a combination of gene discovery and the blossoming of genome-editing technologies such as CRISPR–Cas9 has given this vision of a vaccine-led future for tackling heart disease a strong chance of becoming reality. The breakthrough came in 2003, when researchers investigated three French families with members who had potentially lethal levels of low-density lipoprotein (LDL) cholesterol and who harboured a mutation in the gene PCSK9 1 . PCSK9 encodes an enzyme that regulates levels of LDL — or ‘bad’ — cholesterol. The mutations uncovered in the families increased the enzyme’s activity, raising the level of LDL cholesterol in the blood. Breaking PCSK9, so that the enzyme it encodes loses its function, might therefore reduce LDL-cholesterol levels.

Sensing the possibilities, investigators at the University of Texas Southwestern Medical Center in Dallas sought to determine whether naturally occurring mutations in PCSK9 could also have the effect of lowering LDL cholesterol. The researchers interrogated the Dallas Heart Study, a landmark investigation of cardiovascular health carried out from 2000–02 in 6,000 adults living in Dallas County. The participants recruited represent the three main ethnic groups of the United States. After combing the data from about 3,600 individuals who provided a blood sample, the researchers sequenced DNA from the 128 participants with the lowest levels of LDL cholesterol. They discovered that about 2% of African-American participants had one broken copy of PCSK9, resulting from one of two inherited mutations 2 . A follow-up study of a different, larger population similarly found mutations in almost 3% of African Americans, which was associated with an 88% reduction in the risk of ischaemic heart disease 3 . “I think of them as having won the genetic lottery,” says Kiran Musunuru, who studies human genetic variation and the risk of heart disease at the University of Pennsylvania in Philadelphia.

Musunuru thinks that in the next 20 years, gene editing will enable researchers to confer a mutation in PCSK9, or other beneficial mutations, on people who have had less luck in the genetic sense. “They would be dramatically protected against heart attack and stroke for the rest of their lives,” he enthuses.

Others are more bullish. Technologies for delivering gene editing can be safe, effective and work in the long term, says Sander van Deventer, operating partner at investment firm Forbion Capital Partners in Naarden, the Netherlands. van Deventer played an important part at uniQure in Amsterdam, where he supervised the development of alipogene tiparvovec (Glybera), the first gene therapy to gain regulatory approval. He thinks that gene therapy to reduce the risk of cardiovascular disease could become a reality within 5 years — initially targeted to help people with high cholesterol (a condition known as hypercholesterolaemia).

The liver is a preferred target organ of gene therapy for companies such as Editas Medicine in Cambridge, Massachusetts, Sangamo Therapeutics in Richmond, California, and CRISPR Therapeutics, also in Cambridge it is straightforward to deliver genes to the liver, and the CRISPR–Cas9 tool is especially efficient in the organ, editing a greater proportion of cells than it does in most other tissues. The liver is also an excellent place from which to tackle cholesterol — it clears LDL cholesterol from the blood and is also a main engine of lipid synthesis. “The liver is the gatekeeper for removal of excess cholesterol from the body,” says William Lagor, a molecular biologist at Baylor College of Medicine in Houston, Texas.

The enzyme produced by PCSK9 causes receptors for LDL cholesterol, found on the surfaces of cells throughout the body, to move inside the cell. With fewer receptors available to bind such cholesterol, its level in the blood rises. Already, two antibody-based therapies have been developed to inhibit the enzyme PCSK9, increasing the number of LDL-cholesterol receptors and consequently reducing the amount of cholesterol in the blood. One such PCSK9 inhibitor, evolocumab (Repatha), can cut the risk of heart attack by 27% and stroke by 21%, when administered in combination with statins. But the treatment involves regular infusions of drugs for the rest of a patient’s life and costs about US$14,500 per year, a price that many commentators have deemed too high.

In 2014, Musunuru and his team showed that more than half of Pcsk9 genes in the mouse liver could be silenced with a single injection of an adenovirus containing a CRISPR–Cas9 system directed against Pcsk9. This led to a roughly 90% decrease in the level of Pcsk9 in the blood and a 35–40% fall in blood LDL cholesterol 4 . Next, they used a mouse engineered to contain human liver cells, and tuned the CRISPR–Cas9 payload to target human PCSK9 5 . The team succeeded in showing that the human gene can also be switched off. “I’m convinced that if we gave this therapy to a human, it would work,” Musunuru says.

The approach is “absolutely plausible, even feasible”, from a technological point of view, says Lagor. But there is also a philosophical barrier to negotiate. “You don’t necessarily want to treat people who haven’t got a disease yet,” he says. Karel Moons, a clinical epidemiologist at University Medical Centre Utrecht in the Netherlands, goes further. “Changing lifestyle may be much more effective for a population than focusing on high-cost interventions,” he says. He worries that a gene therapy for individuals at high risk would hinder efforts to help people to help themselves. “It is the way the human mind works. Take a pill and we think we are protected,” he warns.

Musunuru accepts that the idea does not have universal approval but thinks that “there will be greater enthusiasm for human trials for common diseases after genome editing has been proven safe in the patients with grievous genetic disorders”. Debilitating single-gene conditions such as Duchenne muscular dystrophy are likely to be first to benefit from therapeutic gene editing (see ‘Benefits from a partial fix’). Musunuru suggests familial hypercholesterolaemia — the LDL-cholesterol disorder characterized in the three French families — as a similarly logical place to start. The associated mutations in PCSK9 raise LDL-cholesterol levels from birth, causing premature heart attacks — sometimes in childhood — in those who are worst affected. “It would make a lot of sense to knock out the faulty PCSK9 gene in those patients,” he says.

Benefits from a partial fix

Duchenne muscular dystrophy is a single-gene disorder that will probably be in the vanguard of diseases targeted by gene therapy. The condition affects up to 1 in 3,500 boys and men, and causes the progressive weakening of muscles heart-muscle failure is the leading cause of death in people with the disorder. “This disease has resisted every therapy applied to it,” says Eric Olson, a molecular biologist at the University of Texas Southwestern Medical Center in Dallas. “The only reasonable approach is to go to the root cause of the disease, to the mutated gene. CRISPR seems an ideal approach.”

Credit: Patrick Landmann/SPL

At the core of the condition lie defects in dystrophin, a long membrane-associated protein that acts as a shock absorber in muscle cells (pictured). Dystrophin’s central portion comprises 20 or so repetitive sections, which are analogous to the coils of a spring. DMD, the gene that encodes dystrophin, is long, containing 79 coding sections, or exons, and Olson says that mutations anywhere along its length can eliminate the production of functional dystrophin.

Rather than correcting specific mutations, he estimates that 80% of patients could benefit from a partial fix. Some of the coils in dystrophin can be deleted without destroying the protein’s function. This means that sections of DNA within DMD that contain mutations can be removed. The shortened gene will make a working, truncated protein. “One edit can bypass all the mutations,” Olson says.

Dystrophin production as low as 5% of the normal level is thought to improve muscle function Olson thinks that reaching 15% would bring major clinical benefits. In 2017, researchers at the Ohio State University in Columbus blew past that target, restoring dystrophin-expression levels in the heart muscle of mice by up to 40%, simply by slicing out a defective portion of Dmd using a CRISPR–Cas9 system delivered by a viral vector 14 . “So long as the gene can still read out, you make a partially functional protein,” says Renzhi Han, who led the study. His lab is now evaluating the safety of the strategy in mice. Olson’s research group has used the technique to restore up to 90% of normal dystrophin levels 15 .

Han and others are optimistic that trials in people can begin in the next five years. “Duchenne is the most devastating muscle disease. There is no escaping the clinical consequences,” says Olson. “There is enormous excitement in the Duchenne community about this new technology.”

People with hypercholesterolaemia can make changes to their lifestyle and diet, as well as take statins, but this is often not enough. They might also require treatment with antibodies directed against PCSK9 and frequent cleaning of the blood to remove LDL particles. Those with the most severe disease would receive the greatest benefit from genome editing, says Musunuru, and be the first candidates for therapy. “The strongest rationale for using genome editing is that it would be given just once, whereas patients have to take antibodies every few weeks for the rest of their lives.” He views the approach as being particularly useful for people in low-income countries with less-well-funded health-care systems: “I do not see daily pills or monthly injections as being a realistic approach in the developing world.” But although a one-off treatment should be cheaper, drug companies could be tempted to charge a high price, on the basis that it achieves the same effect as do decades of expensive antibody-based drugs.

For now, Musunuru says that we need to work out the safest way to perform gene editing in people — not necessarily CRISPR–Cas9 — and also the best way for it to be delivered. Regulatory approval for a clinical trial would then be required, which could take a few years to achieve.

Since the discovery of PCSK9, other variants in genes that alter the risk of cardiovascular disease have emerged. Some affect triglycerides, the main component of fat in the body high levels of triglycerides in the blood are a known risk factor for heart disease. Apolipoprotein C-III inhibits the breakdown of triglycerides by enzymes a mutation in APOC3, the gene that encodes it, was discovered in a population of Amish people in the United States in 2008 6 . The 5% of the group who were carriers had lower levels of LDL cholesterol, higher levels of high-density lipoprotein (HDL) — or ‘good’ — cholesterol and lower levels of triglyceride in the blood, all of which might reduce the risk of cardiovascular disease. A similar pattern has also been found in people who carry the mutation in Crete, Greece.

Musunuru is optimistic that knocking out a gene called ANGPTL3 can reduce levels of LDL cholesterol and triglycerides. He was part of a team that reported in 2010 on three generations of a family with mutations in ANGPTL3 and that had no history of heart disease and had low levels of cholesterol and triglycerides in the blood 7 . In 2017, three family members who had a complete loss of function of the protein encoded by ANGPTL3 were examined 8 . “As far as we can tell, they are substantially protected against cardiovascular disease, but suffer no harmful consequences whatsoever,” says Musunuru. At least 1 in 300 people has a broken copy of ANGPTL3, which has been shown to reduce the risk of ischaemic heart disease by roughly one-third 9 .

Another potential target is the gene LPA, which encodes lipoprotein (a). High levels of lipoprotein (a) are a main risk factor for heart disease and stroke, yet no treatments have been approved by regulators such as the US Food and Drug Administration specifically to lower its levels. “This really is an ideal candidate for disruption with a liver-directed CRISPR gene-editing approach,” says Lagor. Initial candidates for the treatment would be people with extremely high levels of lipoprotein (a) who also have cardiovascular disease.

The most effective treatments will probably disrupt several of these genes at once to provide the greatest benefit. “Since PCSK9 and ANGPTL3 work by different mechanisms, in principle they should be additive,” says Musunuru. Lagor agrees, adding that there are also economic upsides. “It is likely that the cost of targeting two genes, or perhaps even three or four, would be the same as for one gene.”

Before gene-editing therapy can become routine, two main safety concerns must be addressed. First, off-target effects can occur when the RNA molecule that guides the Cas9 cutting enzyme into position misidentifies its complementary sequence of DNA, resulting in cuts being made in the wrong place. Second, the cellular machinery that repairs the double-strand breaks created in the DNA during gene editing might make an unexpected deletion or addition. Such mishaps could lead to the development of cancer. And although a considerable degree of risk might be acceptable for seriously ill patients with no other option, preventive gene therapy must clear a higher bar. “If the vaccine is being envisioned for the general population, then it needs to be essentially 100% safe,” says Musunuru, “at least to the same degree as the infectious-disease vaccinations that are routinely given to infants and children.”

A new technology from chemical biologist David Liu’s laboratory at Harvard University in Cambridge, Massachusetts, has therefore excited those in the gene-editing field. Liu has developed a technique that uses a modified CRISPR–Cas9 system to alter individual pairs of bases in cells without having to break the DNA double strand 10 . His team was able to chemically change the DNA base cytosine (C) into uracil (a base found in RNA), which the cell later replaced with thymine (T). In 2017, Liu’s team created another tool that could rearrange an adenine (A) so that it resembled a guanine (G), and then hoodwinked the cell into fixing the complementary strand of DNA to make the edit permanent, therefore changing an A•T pair into a G•C 11 .

“Base editing is as big a development as the original introduction of CRISPR–Cas9 to the genome-editing field,” says Musunuru. “It’s totally changed how I’ve been thinking about tackling cardiovascular disease — in a positive way.” He is planning to test Liu’s A-to-G base editor in mice to see how well it works.

Gene-editing researchers have embraced targeted base editing to install precise changes without the uncertainty that accompanies a double-strand break. The technique has been used in labs to correct genes in yeast, plants, zebrafish, mice and even human embryos. A proof-of-concept study by Alexandra Chadwick, a postdoctoral researcher in Musunuru’s lab, delivered a base editor into the livers of adult mice to disable Pcsk9, halving the level of Pcsk9 and cutting LDL cholesterol by almost one-third 12 . Musunuru adds that he has preliminary results showing base editing of Angptl3 in mice using Liu’s C-to-T method.

More from Nature Outlooks

The pace of innovation in gene editing has created an aura of optimism, particularly around the treatment of people with genetic disorders who have few or no other options. “It makes sense to begin therapeutic efforts with such diseases, even if the understanding of all potential risks is imperfect,” says Liu. But there is the potential for the technique’s use in the clinic to spread beyond these testing grounds. van Deventer has successfully lowered LDL cholesterol in mice by silencing apolipoprotein B-100 using a method called RNA interference 13 he sees great potential in using the microRNAs that underpin the technique and, eventually, gene editing to address heart disease. “ANGPTL3, PCSK9 and APOC3 are targets not easily addressed by small molecules or antibodies,” he says. And the one-off nature of gene-editing treatments cuts down on issues with patients not following advice about when to take a drug — a perennial problem concerning people on long-term medication.

“If you are talking about cardiovascular disease as a global health threat, which it undoubtedly is, then protecting the entire population is what we need,” says Musunuru. Lifestyle changes are important, but a substantial portion of the risk of heart failure and stroke comes from the genome. “You don’t need to choose between medicine and lifestyle. You should be doing both,” says Liu, citing people with diabetes, who fare best when they take medication and adjust their lifestyle.

“To vaccinate large numbers of people, that is some way off,” says Musunuru. But gene editing could reset the odds for those who didn’t win the genetic lottery, he predicts. “One way or another, genome editing is going to underlie a host of new types of cardiovascular therapies over the next 25 years.”

Nature 555, S23-S25 (2018)

This article is part of Nature Outlook: The future of medicine, an editorially independent supplement produced with the financial support of third parties. About this content.


Introduction

Advanced technology made us to live sedentary lifestyle and due to this kind of lifestyle we all are in high risk to develop heart diseases in life time. Less physical activities, increased alcohol consumption and use of tobacco products leads to heart diseases (Figure 1).

Important Warning Signs Includes

Lightheadedness, Nausea, extreme fatigue, fainting, dizziness, Pressure in the upper back [1]. Other symptoms of a heart attack can include: Extreme anxiety, Fainting or loss of consciousness, Lightheadedness or dizziness, Nausea or vomiting, Palpitations, Shortness of breath and Sweating, which may be very heavy [2].

Important Statistical Information of CVDs

a) "CVDs are the number one cause of death in the world: more people die annually from CVDs.

b) 17.7 million People died from CVDs in 2015, representing 31% of all global deaths. Of these deaths, an estimated 7.4 million were due to coronary heart disease and 6.7 million were due to stroke.

c) CVD deaths take place in low and middl income countries.

d) People with cardiovascular disease or who are at high cardiovascular risk need early detection and management using counselling and medicines, as appropriate [3].

e) 㹵% of CVD deaths occur in low-income and middle- income countries"


Quest Diagnostics to accelerate cardiovascular disease biomarker discovery as part of One Brave Idea™ initiative to end coronary heart disease

CHICAGO, Nov.11, 2018 — Developing novel approaches to understand cardiovascular health and pre-disease is the cornerstone strategy of One Brave Idea™, a research initiative led by Dr. Calum MacRae, vice chair for Scientific Innovation in the department of Medicine at Brigham and Women’s Hospital.

In a move to advance the ground-breaking work to identify coronary heart disease at the earliest transition from wellness to disease, Quest Diagnostics (NYSE: DGX) will contribute biomarker implementation, population health analytics and a national lab platform as a pillar supporter of One Brave Idea, the research initiative co-founded by the American Heart Association (AHA) and Verily Life Sciences with significant support from AstraZeneca.

“As the leader in cardiovascular diagnostic insights, Quest Diagnostics brings a remarkable network of just-in-time clinical and consumer diagnostics, access to rich longitudinal data and the logistical framework to quickly translate science into actionable insights for the people who seek ways to pre-empt heart disease,” said Nancy Brown, American Heart Association chief executive officer, who announced the news today from the stage in Chicago at the organization’s 91st annual Scientific Sessions, the ultimate assembly of global influencers in cardiovascular research and medicine. “There is great value in bringing Quest Diagnostics biomarker development experiences to One Brave Idea research that has the potential to predict early signs of coronary heart disease.”

The One Brave Idea team includes experts from a diverse background, including engineering and data sciences as well as many prestigious institutions such as Brigham and Women’s Hospital, Stanford University and Northwestern. One Brave Idea is working to create a coronary heart disease early warning system by investigating what happens 10-20 years before any risk factors typically appear. A key aim is to develop novel diagnostic techniques to identify cardiovascular disease, including stroke, in stages where discreet forms can be identified, and preventive measures initiated to stop or reverse disease progression.

“We share the commitment of One Brave Idea and its member organizations and scientists in establishing the path to heart disease prevention,” said Steve Rusckowski, chairman, president and CEO for Quest Diagnostics and a member of the American Heart Association CEO Roundtable. “For far too many people, the first sign of heart disease is a fatal event, such as a myocardial infarction (heart attack) or stroke. Our collaboration in One Brave Idea aims to change that. Quest Diagnostics brings robust biomarker and medical expertise, population health analytics and national presence to accelerate discovery of early disease biomarkers and biology changes and fast-track prevention measures that can create a healthier world.”

Consumers are more engaged in their health than ever before and healthcare innovation is happening at every corner, opening up a whole new world for evidence-based diagnostics that can be broadly scaled across hospitals and clinics for real-world implementation.

Quest Diagnostics will provide state-of-the-art diagnostic services and population health analytics in support of OBI research. Through its Cleveland HeartLab, Quest Diagnostics maintains a pipeline of early-stage genetic and biological markers in cardiometabolic disorders with the potential for future diagnostic services for clinical use and pharmaceutical research.

Additionally, Quest Diagnostics deep biomarker expertise and rich dataset of de-identified laboratory testing on millions of patients for cardiovascular, metabolic and other disorders is expected to inform OBI research. Quest Diagnostics also maintains avenues to directly engage patients and providers, a common impediment to scale research. These avenues include Quest Quanum™ connectivity to about half the physicians in the United States, a network of 2,200 patient service centers, and the MyQuest™ patient app, which has six million subscribers.

“Through Verily’s informatic capabilities, AstraZeneca’s proprietary data, the AHA’s ecosystem of patient centered research and scientific networks and now Quest’s diagnostic expertise and rich datasets, we will enhance our progress toward ending coronary heart disease and its consequences,” said MacRae.

Heart disease is the number 1 killer worldwide. Stroke ranks second globally and is the leading cause of severe disability. An estimated 17.7 million people die from cardiovascular disease annually, representing 31 percent of all global deaths. Precision medicine offers the promise of better patient outcomes through earlier prediction of disease and targeted treatments for individuals.