As the "machine" of the human body, the heart is truly a miracle: it beats 100,000 times a day and does not stop for decades. Everyone knows the importance of the heart and understands the threat of heart disease, yet as the mortality curve of heart disease gradually flattens out, this has forced scientists and doctors to discover more mechanisms that damage the heart, which are hidden in life and genes. We have even fallen victim to successful medical treatment – the success of chemotherapy treatment for cancer has destroyed the already scarce heart muscle cells. Heart health challenges remain.
This article is excerpted with permission from Chapter 2, "Threats to the Heart: 1000 Natural Shocks" in Guarding Your Heart (CITIC Publishing House, March 2024 edition).
Written by | Shane S. E. Harding
Translation | Xu Yunyun
Proofreading | Li Qingchen
There's a good chance you, or someone you know, have been plagued by heart disease, which is the leading cause of premature death worldwide. Globally, cardiovascular diseases (including coronary heart disease, stroke and vascular dementia) account for 32% of deaths, and surprisingly little difference between developed regions, with 29% in the UK, 43% in Europe, 32% in the US and 33% in Asia. In general, cardiovascular disease is the same as cancer, but people over the age of 75 are more susceptible to cardiovascular disease.
There is a notion that death from a heart attack is a quick and merciful death, and for a few people it may be true, and a violent heart attack or sudden severe arrhythmia will at least pass quickly. However, heart failure is a process that gradually worsens until chronic breathing difficulties develop and are debilitating. If a heart attack is like being hit in the chest, heart failure is more like being submerged or suffocated. After seeing firsthand how this terrible disease affected my father-in-law and my family, I chose to study heart failure.
Disturbingly, the incidence of heart failure is gradually increasing in most parts of the world. Currently, about 6.2 million adults in the United States have heart failure, and about 1 in 2 die within 5 years of diagnosis. Heart failure is slow and fatal, with a lower survival rate than most cancers. Like cancer, its progression tends to accumulate through a series of emergency admissions and apparent remission. Increasingly, we are discovering that it is the many threats facing the heart that push it to the point of failure, some of which are external injuries that have only recently been discovered, and others that are deeply rooted in our evolutionary history.
First, let's talk about the good news. Over the past 50 years, the number of deaths from heart attacks and strokes has declined dramatically (Figure 1), especially in younger groups.
Figure 1 Mortality from heart disease has been declining since 1969
This dramatic change is driven by the "twin engines" of prevention and rapid treatment. The way we live has changed dramatically, and public health initiatives have played a huge role in deserving mention: anti-smoking campaigns, screening and treatment for hypertension, dyslipidemia and diabetes, and encouraging exercise and healthy eating patterns. We're seeing results, and sometimes they happen faster than you think.
We now know that the damage caused by a cardiovascular blockage can worsen in a matter of minutes to hours, and hospitals have set up fast-track or specialized heart centers. We would say that "time is the heart muscle". When you call the emergency services for chest pain, the operator will prioritize your call and provide you with help as soon as possible. In fully equipped ambulances, paramedics provide direct emergency medical care. When you arrive at the hospital, you'll be taken directly into the cath lab, where the doctor will remove the blockage and place a stent in the problematic vessel to keep it open. Subsequently, your doctor may replace the blocked blood vessel with a new one that has been transplanted. These well-designed protocols have reduced mortality and improved outcomes for heart attack patients. In the 10 years before 2010, the survival rate of heart attack patients in the UK rose from 75% to 85%, and there was a similar change in the US.
However, despite these improvements in heart health, the mortality decline curve shown in Figure 1 has begun to flatten out, and the exact reasons are not yet fully understood. It may be that the low-hanging fruit of victory has been reaped: the most impactful measures, such as fast-track treatment pathways and available drugs (statins, ACE inhibitors, etc.), are already in place. Other behavioral changes, such as more exercise, healthier eating, better sleep, take a while to integrate into the culture. Moreover, there are biological and social barriers that are thwarting our own best intentions and thwarting government efforts to make our lives healthier.
Health inequalities start before birth
The threat to the heart does not only come from the external environment, but there may also be a time bomb hidden in our body. When we fight infectious diseases, or make progress in eradicating extreme poverty and child deaths, or control acute heart disease and cancer, we live longer, healthier lives with a long history of "genetic betting." Genetic analysis is now cheaper and more widespread, so much so that comprehensive screening of genes will soon become a standard part of medical testing. While you might think that heart mutations are deadly, in fact they are surprisingly common. What we know may be just the tip of the iceberg.
Scientists study families with obvious signs of hereditary heart disease (enlarged or malformed hearts, irregular heartbeats) and screen their genomes to find the mutations that cause the problem. There is a perplexing finding: different family members may have the same mutation, but the symptoms are very different, with some severely affected and others completely unaffected. Researchers are tracking down the cause of this discrepancy, and the answer could be a "second whammy", or an additional burden, either a change in an individual's lifestyle or a second genetic mutation. Although this second blow itself may have only a slight or imperceptible effect, it can double the risk of mutations. Its presence makes the way the disease manifests itself differently and can even determine whether the disease itself exists.
One of the most striking examples of the effects of "second strikes" is mutations in myaunectin, also known as myomegalin. Myonexin is the "spring" that relaxes heart muscle cells between heartbeats, and it is one of the longest proteins in the body when stretched. Cardiology geneticists studied people with heart failure unrelated to a heart attack (dilated cardiomyopathy, in which the walls of the heart are stretched and thinned) and found that up to one-quarter of the lesions were caused by mutations in moneectin. It seems clear that this is a very serious mutation. But when scientists began looking at a large number of healthy-looking people and thought they wouldn't carry the mutation, they were shocked. One of the studies was conducted at Imperial College London, where about 2,000 volunteers underwent magnetic resonance imaging of the heart and whole-genome sequencing. Shockingly, researchers found that about 1% of these subjects also had munitin mutations. This ratio corresponds to the U.S. population, meaning that as many as 2.5 million people carry an undetected mutation.
With munitin as the first clue, scientists have been looking for a second clue that makes people sick. This is a very new work, but we have seen more than one (and several) triggers that reveal the hidden weaknesses of the heart. Cancer drug treatment also carries risks, and the combination of myennectin mutations can increase the likelihood of heart problems. Cancer survivors who have heart damage are more than 10 times more likely to have a myogenic mutation and develop more serious heart disease.
Alcohol is another trigger. One bright spot in the statistics: Contrary to the trend towards strict self-discipline, there has been evidence that moderate drinkers are less likely to die of heart disease than non-drinkers. Admittedly, over the years, the definition of "moderate" has shifted from "drinking less than your doctor" to a more specific, ever-decreasing number of units of alcohol, but the basic observation has been hard to shake. To the dismay of drinkers, however, the latest research suggests that it depends more on genes. The researchers found that the incidence of monenectin mutations was higher in patients with true alcoholic cardiomyopathy who drank more than 10 drinks per day for several years. Most people don't drink that much, so we may feel like we can let our guard down. In patients with unexplained dilated cardiomyopathy, a simple myonexin mutation or moderate alcohol consumption in excess of guideline recommendations is not a significant predictor, but the magnitude of cardiac decline in patients with both risk factors is worrying. That is, these people are pushed to heart failure by drinking, while others may be fine with drinking.
It's not just chemicals that can put pressure on the heart. Pregnancy is a normal physiological process, but how much stress it puts on the heart is not widely known. In order to carry oxygen and nutrients to the growing baby, the woman's body has a 50% increase in blood volume, and the mother's heart works harder and beats faster to keep the blood circulating. Blood pressure drops because hormones during pregnancy cause blood vessels to relax and dilate. Childbirth is further stressful both physically and emotionally, and changes in blood pressure during the exertive phase of labor are one of the most extreme conditions experienced by pregnant women. After childbirth, it takes a few weeks for the stress on the heart to return to pre-pregnancy levels. Some women say they are too anxious to cope after pregnancy and childbirth, and here's why.
Most women go through this period with some form of physical discomfort, but recover quickly. However, there is a condition known as perinatal cardiomyopathy, in which a woman unexpectedly develops heart failure in the late stages of pregnancy or shortly after childbirth. Geographically, the incidence may be as high as 1 in 100 in most common areas, including Nigeria and Haiti, and between 1 in 4000 and 1 in 1000 in Europe and the US. If an expectant mother is pregnant with twins, is older or overweight, or has preeclampsia and has a sudden increase in blood pressure, she is more likely to develop perinatal cardiomyopathy. Despite recovery, up to 1 in 10 people die in the United States, and an increasing number of women require heart transplants to treat perinatal cardiomyopathy. Now we know that another risk factor for this disease is a hidden mutation. In one study, affected women were 6 times more likely to have a munitin mutation than women in a control group. I will say it again, the disease is always dormant until pregnancy and childbirth bring a second blow.
Myonexin is just one of the mutations we know of, and the mutation that causes dilated cardiomyopathy is found in 1 in 250 people. In fact, in terms of the entire body (not just the heart), it is estimated that each person carries about 400 potentially damaging DNA (deoxyribonucleic acid) variants and 2 mutations known to be directly related to the disease. Up to 1 in 10 people may develop a genetic disorder because of these variants. It's sobering to think that these time bombs hidden in our genes can turn everyday challenges or choices into unforeseen dangers.
Worse
All of the factors that can cause heart damage or dysfunction have the same goal, and eventually they weaken the heart's ability to pump blood. Instead, the final blow was caused by the body's response to impaired cardiac output, which pushed the heart off a cliff and plunged it into a syndrome known as heart failure.
Heart failure is not the same as a heart attack. While a heart attack is one of the "damages" that can cause heart failure, its symptoms vary widely. We all deserve to know the symptoms of a heart attack, so I'm going to count them here: sudden pain or discomfort in the chest that persists and may spread to the left or right arm, or to the jaw, back, upper abdomen, and may feel nauseous, sweating, dizzy, or short of breath. In this case, you will need to call the emergency center directly. Heart failure is not acute but is more insidious, with the main signs being chronic dyspnea, fatigue, and swelling of the ankles.
Heart failure is basically a spiral of damage that is driven by the body itself through the action of hormones and neurotransmitters and is initiated by the first damage: the first damage could be a heart attack, medication, or infection. Because of tissue ischemia, the body senses that the heart is being drained of its strength and immediately reacts to protect itself. However, the body misinterprets these signals because humans didn't live long enough to even wait for a heart attack when they evolved this mechanism and died before they even had a heart attack, when the most common life-threatening was trauma.
In heart failure, the patient's body reacts as if it has been deprived of blood supply to tissues by trauma and blood loss, so the primary goal is to preserve water. The lungs and kidneys work together to produce two hormones, angiotensin II and aldosterone, which constrict blood vessels and reduce the amount of water lost through the urine. Epinephrine and norepinephrine stimulate the heart to pump blood faster and stronger, and further constrict blood vessels. The patient's body is soaked with body fluids, which accumulate in the lungs make it difficult to breathe, fluid that accumulates in the intestines disrupts the digestion process, and fluid that accumulates in the extremities causes swelling. No wonder heart failure feels like drowning.
At this point, the second spiral also kicks in, and we are just beginning to understand this low level of immune activation and inflammation that persists after the initial injury. After a heart attack, a sharp influx of inflammatory blood cells begins as a response to the extreme emergency of devastating heart damage. Subsequently, the damage is replaced by scarring, and the flame of inflammation continues for months to years. This is the body attacking itself. Normally, the body recognizes which proteins are "its own" and which are "not" and responds immunally to foreign invaders. The classification function of identifying "one's own person" is done in the thymus gland before birth, when anything present in the body is recognized as "one's own person" and is thereafter ignored by the immune system. But some proteins inside heart muscle cells are not present before birth, and they mature later. When heart muscle cells die, they are released, they are recognized as "not their own" and trigger an immune response that makes antibodies against heart proteins. They attack heart cells, leading to ongoing inflammation and cell death. Big data from large heart attack patient populations show that inflammation at the lowest detectable level, once thought too small to be dangerous, can be used to accurately predict premature death in those with heart damage.
Now, all of our medications for heart failure patients are designed to break the vicious cycle of neurohormone activation, which increases circulating hormone levels when the body tries to stimulate a failing heart. These include β blockers that block adrenaline from working, blockers that target angiotensin II and aldosterone, diuretics that drain excess water, and of course, drugs that prevent more damage, such as statins that lower cholesterol levels, aspirin, which is anti-thrombotic and anti-diabetic drugs. If you only look at clinical trials, you will find that these drugs are all performing well, and each drug has shown that the survival rate of patients has increased by 10%~20% within two or three years after use. New drugs are also beginning to be successful in blocking inflammation and immune responses, but at the same time it is difficult to achieve balance to prevent the body from becoming susceptible to infections.
However, as trials get bigger, the benefits get smaller and smaller. Each new drug must be tested against the best combination of existing drugs. (In fact, it's often said that there are benefits to being put on a placebo in a clinical trial, which ensures you get the best treatment available.) Each time a new drug is tested, the size of the test population must be expanded in order to detect small improvements, making new cardiovascular trials prohibitively expensive. As revenues begin to dwindle, large pharmaceutical companies are pulling out of the cardiovascular disease drug segment. Finally, there is currently no cure with a single drug. None of the drugs can reverse the initial damage: they can only try to delay the progression of secondary damage from the body's defense system, and none even do (or at least safely) stimulate the surviving cardiomyocytes to work harder.
Thrifty genes
In addition to trauma, another major threat in our evolutionary history has been starvation. At this point, our biological mechanisms reacted violently to this potential danger, so much so that it paradoxically gave birth to one of the greatest dangers to the heart and blood vessels of all time.
In most parts of the world, the number of diabetics is increasing at a plague rate. In the United States, more than 1 in 10 people have diabetes: this number has tripled since 1980 and is estimated to double again by 2060. The disease itself is associated with blood sugar control. Insulin is responsible for bringing glucose (the main blood sugar) into tissues to use its energy, and type 1 diabetes is caused by an absolute lack of insulin, while type 2 diabetes is insensitive to insulin by pancreatic islet target cells. The result is an increase in blood sugar levels. This not only leads to the typical symptoms of excessive urine production, but also to damage to blood vessels, especially tiny ones. All tissues have blood vessels, so they can be damaged. Damage to blood vessels leads to a decrease in oxygen delivery to tissues, which is the reason for the high rate of leg amputation in people with diabetes. But the heart is particularly sensitive because of its high oxygen demand, and more than two-thirds of deaths in people with diabetes are caused by heart disease.
To explore the reasons for the sudden increase in the number of people with diabetes, the clues come from different groups of people who have gone through difficult times. Aboriginal people in places like Australia and others with long migration experiences tend to suffer from diabetes and heart disease extensively. Of course, the triggers of type 2 diabetes are food overload, obesity, and especially the Western way of eating. But in people who have been deprived of food, the consequences of having adequate access to a high-calorie diet are much more severe. What's more, it's not the hungry people themselves who become obese and develop diabetes, it's their children. A child in the womb perceives the environment through the mother's body: he or she prepares for what he or she faces after birth by adapting their DNA through chemical modifications known as epigenetic markers. If the mother starves during pregnancy, the child is deprived of nutrients and is born with a low body weight. Their genes will be adjusted to tend to gain weight as quickly as possible and keep it up. This is known as the "thrifty gene hypothesis". In many different cases, low birth weight is strongly associated with later development of diabetes and cardiovascular disease.
If a child is born into a world where food is scarce, then these genetic modifications are excellent for their survival. If the child is born across the street from a shopping mall with 20 fast food outlets, you can see what the problem is. Epigenetics are influenced not only by biochemical changes related to calorie retention and storage, but also by behavioral changes, such as craving high-calorie foods, eating too much, and conserving energy by avoiding exercise. The rapid westernization of large countries like India, combined with food scarcity in recent history, is the biggest cause of the current diabetes outbreak. The era of famine in Europe has long passed, so the increase in cases is not so fast. However, epigenetic markers are preserved not only in the children of those who have suffered from food insecurity, but also in their grandchildren, so diabetes will be susceptible for generations.
We are victims of our own achievements
In addition to these threats, which are deeply rooted in the evolutionary process, we now face new dangers that are emerging. Some of them even come from our efforts to treat other diseases: cancer is an example of which we have found accidental damage to the heart in its treatment. Oddly enough, the heart has hardly ever had cancer, so cardiologists and oncologists don't have any tangible topics to talk about. So, it took some time for oncologists to realize that their success story, a patient who had achieved long-term remission after cancer treatment, developed a heart attack.
Of course, both cancer and heart disease become more common as we age, so it's thought that having both diseases at the same time is just bad luck. The case of breast cancer highlights the fact that this is not just a statistical anomaly, but a causal relationship between cancer and heart disease. This judgment is based on two reasons. First of all, the treatment of breast cancer has been very successful. For women whose cancer is confined to the breast, the 5-year survival rate is about 99%. In the case of invasive cancers, the 5-year survival rate is still 95% (which is good), and the 10-year survival rate is 83%. This means that many women are now undergoing chemotherapy and are being effectively cured. As a result, the prolongation of life makes it possible for them to develop heart disease, and indeed more people show signs of heart disease. Second, women are generally less susceptible to heart disease, so the unexpected spike in heart problems is more dramatic. This alerted oncologists to look into the issue further. By carefully studying and analyzing data from well-controlled clinical trials, they found that treatments for breast cancer (in fact, for any type of cancer) have the potential to damage the heart. The treatment of one disease triggers another.
The older generation of anti-cancer drugs is simply a cellular poison, destroying everything in its path. They are better at killing fast-dividing cells, which is why they work against cancer, but they leave traces of damage to all body systems. Your hair is the first victim of chemotherapy: it's the fast-dividing cells in the hair follicles that keep the hair growing. The heart muscle itself has very few cells that are dividing, so any loss will have a violent effect. Of course, as I've always emphasized, your heart doesn't have a backup. Some of these older (but still very useful) drugs have caused heart damage in many patients. At the highest dose, almost 1/2 of patients treated with one major chemotherapy drug developed heart failure. Radiotherapy also works largely by killing the most active cells, and there is also a risk of heart disease. But we can't dismiss these therapies just because they have side effects – they have successfully treated cancer, and that must be our top priority.
When a new generation of anti-cancer drugs emerges, clinicians want the problem to be solved. These drugs attack cancer in a variety of ways: some cut off the blood supply to tumors by interfering with the development of blood vessels, others use antibodies, just like our body's natural molecules that recognize infection, to detect specific markers on cancer cells and combine them with the latest checkpoint inhibitors to go a step further and harness the power of the body's immune system to attack cancer cells. To the disappointment of oncologists, they found that while these new drugs dramatically improved the survival of patients with pain, patients still suffered from heart disease. To make matters worse, combining a new drug with an old drug can make the effects of the old drug even more deadly.
It seems that good medicine for cancer is bad for the heart and vice versa. Cancer is the most extreme example, where cells get out of control, divide rapidly, and sneak through the body. The heart is the opposite: cardiomyocytes are among the least likely to divide or leave the very strong anchor points in the heart wall. Drugs to treat cancer have taken away the few remaining dividing cells in the heart, weakening its already weak ability to repair. The tumour actively attracts blood vessels into its body to meet its rapidly growing needs. The heart is also an organ with highly developed blood vessels because it has a constant and huge demand for energy. Some pain-fighting drugs work by blocking the tumor's blood vessel growth, but this also affects the blood supply on which the heart is so strongly dependent.
It can almost be said that as we age, we walk a tightrope between the uncontrolled chaos and expansion of cancer and the dying and degeneration of the heart, which is unable to wake up cardiomyocytes to divide and save itself after being damaged.
Cancer treatment is not the only classic case of adverse effects on the heart. HIV (Human Immunodeficiency Virus) infection, also known as AIDS, went from a death sentence to a chronic disease that can be carried out with the disease. However, both the disease itself, and the drugs that control it (how ironic it is), can make people fail. In the advanced stages of AIDS, many infections caused by the disease, as well as large amounts of HIV in the blood, can bring about a severe deterioration of the condition of the heart muscle. However, the administration of new antiretroviral drugs amplifies traditional risk factors for cardiovascular disease – hypertension, poor lipid profile, obesity and diabetes. Add to that the undercurrent of infection and inflammation and the effect is enhanced. The likelihood of myocardial infarction is increased by 50% and the likelihood of heart failure is doubled. Other cardiovascular diseases, such as pulmonary hypertension and atrial fibrillation, have also become more common. In countries where AIDS is endemic, drug treatment has made the disease increasingly manageable, and health care systems have had to be strengthened to deal with the explosive increase in the number of heart patients.
For cancer and AIDS patients, treating the disease itself is an absolute priority. At the moment we can only accept the side effects of drugs, but scientists and clinicians are putting a lot of effort into avoiding these problems. All new cancer drugs are tested for cardiotoxicity to assess their risk of heart damage. This is the standard for drug development, and cardiovascular side effects result in many potential drugs being removed from the development pathway before they are marketed. Pharmaceutical companies are also seeking new chemotherapeutic drug designs and combinations that can eliminate cardiotoxicity while maintaining a strong anti-cancer effect.
Clinicians, on the other hand, monitor cancer patients very carefully to catch the first signs of heart disease. Large cancer hospitals are establishing links with cardiovascular centers to set up clinics where cardiologists and cancer specialists work together in order to protect the heart while attacking malignant tumors. Oncologists and cardiologists are working together to learn from each other's expertise. Going forward, cancer patients will be closely monitored for cardiovascular disease risk factors and may even be prospectively administered drugs to treat heart failure. Clinically, guiding patients along the way between these two major diseases with conflicting treatments is a new tightrope thing.
Incurable diseases are numerous
Heart failure is defined as a syndrome caused by a deficiency in heart function that can be identified by a range of symptoms. You'd think that from this point of view, it's hard to get it wrong, but heart failure has symptoms of breathlessness and fatigue that can easily be confused with other diseases, such as chronic obstructive pulmonary disease (COPD). Moreover, heart failure can and often coexists with COPD and other geriatric diseases. Chronic disease coexistence, in which multiple underlying conditions are intertwined, is the norm rather than the exception for today's seniors. Is it just because of stiff joints or the start of a more serious illness that an elderly parent can't make it to the store, or is it the beginning of a more serious disease?Diabetes, fatty liver, kidney problems, arthritis, dementia are all common, they overlap with each other and have many common risk factors. Inflammation is again a key underlying cause of this condition, accelerating the development of the deplorable features of the aging process, such as muscle atrophy and weakness. Almost 1/2 of people aged 65~69 have two or more chronic diseases, and among people aged 85 and above, this proportion increases to 75%.
Our medical system produces specialists with an in-depth understanding of a single organ system (eye, lung, kidney, etc.), which naturally prevents us from making comprehensive diagnoses of these patients. For patients who come to the hospital with shortness of breath, being diagnosed with heart failure or COPD can be a matter of luck – depending on which specialist has the time at the time. The same problem exists when we study diseases in universities and medical schools: because of the division of departments, scientists from different fields never meet. We're starting to realize this and we're working hard to combat it, including funding cross-disciplinary research, designing buildings that drive people with different expertise, and training students in multiple fields. It's hard work, with institutional barriers to overcoming and coordinating the ever-expanding volume of information, but we have to do it in order to understand the disease holistically.
Scientific discoveries in many fields are emerging that need to be used to combat the growing threat to the heart. The basic dynamics of the heart and blood flow are well known, but now we can look farther and deeper, from the myocardium as a whole to individual cardiomyocytes, from individual cells to intracellular organelles with special functions (such as the nucleus), and deep into the nanodomains where individual molecules aggregate and interact. Each new advance in microscopy brings us to a new and complex world. Chemistry gives us the tools to measure the changing distances between molecules – they sometimes dance together and sometimes apart. In order to understand the true perfection of the heart, we must now visit the microscopic realm that visible light cannot perceive.
About the Author
Shane S. Sian E. Harding: Professor Emeritus of Cardiac Pharmacology at the National Heart and Lung Institute at Imperial College London, who has been researching cardiac science for decades;
About the translator
Xu Yunyun: Doctor of Clinical Medicine, popular science writer, loves to be a porter of knowledge, has translated many books such as "Rush to Mars", "DK Pregnancy Encyclopedia", "Wolf King Tetralogy" and so on, focusing on promoting a healthy lifestyle and related public welfare undertakings.
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