Has COVID set us up for a major heart disease epidemic? It’s happened before

Over the first half of the 20th century the world saw growing rates of heart disease mortality. From the 1920s to the 1960s more and more people were dying from heart attacks. It was described as an epidemic of heart disease. But in the mid-1960s heart disease mortality suddenly plateaued.

In the United States, for example, around 35% of overall deaths could be attributed to cardiac causes in 1966. From that point on heart attack mortality began to dramatically drop. By the mid-1990s overall deaths in the United States due to cardiac causes was almost half of what it was 30 years prior.

This rise and fall of heart disease mortality in the 20th century still remains a mystery to researchers. The numbers can’t be explained by improvements in medicine and medical care. In fact, as rates of obesity increased in the later part of the century and processed food became more unhealthy, heart disease mortality realistically should have continued to rise.

One researcher, writing about the mystery in 2012, suggested the decline of the 20th century heart disease epidemic cannot be effectively explained by dietary or physical factors. Instead, there must be an unknown environmental biological factor at play.

“The epidemic is now virtually at an end, but we are left with the question, has CHD [coronary heart disease] been due to an environmental biological factor, which is a micro-organism, a bacterium or a virus? If so, it has not been clearly identified, but it has never been fully investigated,” writes D.S Grimes.

Fallout from the flu pandemic Around 20 years ago a pair of epidemiologists presented a controversial new hypothesis to explain this weird phenomenon: the 1918 influenza pandemic triggered a wave of heart damage in millions of people and primed them for later-life heart disease.

The research suggested a decline in H1N1 influenza activity over the decades following the 1918 pandemic correlated with a later drop in cardiac mortality. The hypothesis was that a combination of the virus circulating less and potential changes to the way the disease affects cardiovascular health in a host led to the overall decline in heart attack deaths over the later decades of the 20th century.

Unsurprisingly, this hypothesis has been fiercely debated by researchers over the past couple of decades. A detailed dig into the epidemiological data in 2016, from a trio of US researchers, found the connection between the 1918 pandemic and trends in mortality to be, “not congruent with the available data on long-term changes in heart disease mortality.”

In other words - yes, there has been a dramatic rise and fall in heart disease mortality over the 20th century but, no, it is unlikely to be related to the 1918 flu pandemic. More recently, epidemiological research has focused explicitly on the possible long-term effects of prenatal H1N1 exposure during the 1918 pandemic. Here, researchers looked specifically at what happened in the long-term to those either still in the womb or just born around the years of 1918-19.

A compelling 2009 study compared the 1919 birth cohort to those born just before or just after the period of the acute pandemic. Across a variety of benchmarks the researchers found significant long-term health complications were more prominent in the 1919 cohort. After the age of 60 the 1919 cohort were found to have 25% more incidences of heart disease, plus lower levels of educational attainment compared to other cohorts. “The fact that this cohort of people had elevated risks of disease even more than six decades after the pandemic indicates that maternal exposure to the influenza virus appears to have had wide-ranging and long-lasting health effects on offspring,” said Eileen Crimmins, one of the co-authors on the study, in a 2020 interview.

These studies are, of course, subject to a whole host of limitations, not the least of which being they can only look at overall population trends and not actually quantify which children were directly exposed to influenza while in the womb and which were not. The conclusions are based on the idea that the virus was so prevalent during 1918/19 that it is likely most babies were exposed.

Interestingly, the data is not limited to US birth cohorts. Subsequent studies have looked at long-term outcomes from birth cohorts born during the flu pandemic in both Taiwan and Sweden. Similar patterns were noted from increased rates of long-term health problems to lower levels of educational attainment.

Human hearts meet SARS-CoV-2 SARS-CoV-2 is a very different virus to influenza. In many ways it is much more problematic. It can infect a far wider assortment of human organs and tissues than influenza and it is mutating in ways very different to H1N1. The COVID pandemic has not waned and dissipated in the same way the 1918 pandemic did. Instead, the SARS-CoV-2 virus is frantically changing its form from month to month leading people to experience relatively frequent reinfections. This constant exposure to the virus may be amplifying its long-term impact, but of particular interest is the potential impact this could have on our hearts. A recently published study from Japanese researchers laid out exactly how SARS-CoV-2 can infect and damage the heart. The researchers concluded with a stark warning: we may be facing a looming heart disease epidemic over the coming decades.

In order to infect someone the SARS-CoV-2 virus first needs to track down cells harboring a particular kind of enzyme. Called ACE2, this enzyme acts a bit like a doorway into the cell for a coronavirus. The virus’s spike protein binds to ACE2, allowing the pathogen a pathway into the cell’s inner machinery.

In news that will surprise nobody, ACE2 receptors are all over the epithelial cells that line our nose, mouth, lungs and airways. This is how COVID manifests in the illness that most people are now quite familiar with.

But ACE2 receptors are not isolated to those particular respiratory cells. ACE2 can be found all over the body in a wide variety of organs – and this receptor is found in relatively high volumes on cells inside our heart.

Early warning signs Early on in the pandemic doctors started to see a significant uptick in patients presenting to emergency rooms with acute heart problems. In the first eight weeks of the pandemic hitting New York City in early 2020 paramedics had to deal with three times the rate of nontraumatic out-of-hospital cardiac arrests compared to the same time period in 2019. Similar data was coming out of other regions hit in the earliest phase of the pandemic. In Northern Italy, for example, out-of-hospital heart attacks spiked by 58% across those initial months in 2020.

An early warning report from a team of doctors in New York City published in April 2020 noted distinct signs of heart tissue injury in a number of deceased COVID patients. This virus was doing something to our hearts. As more time passed, and longer-term studies accumulated, it became clear that SARS-CoV-2 infections notably affected a person’s heart health. Waves of infections correlated with waves of heart attack deaths. In the 12 months following a bout of COVID people were five times more likely to suffer from myocarditis and twice as likely to experience a heart attack. Even recovered COVID patients were showing longer-term signs of heart damage. But why were people facing a persistent risk of heart disease in the months, and perhaps years, following a case of COVID? Could a short-term infection with SARS-CoV-2 be causing a kind of long term damage to heart tissue that elevates one’s risk of cardiac complications?

Possibly. But another hypothesis started to emerge. Maybe the virus was becoming a latent infection – sitting quietly in heart tissue and slowly degrading a person’s overall heart health?

The lingering virus To investigate this idea, a team of researchers, including Hidetoshi Masumoto and Kozue Murata from the RIKEN Center for Biosystems Dynamics Research, created a three-dimensional cardiac model in the lab using human-induced pluripotent stem (iPS) cells. This led to what the researchers describe as a “vascular network-like structure that morphologically and functionally mimics the human heart.”

The cardiac tissue model was then infected with SARS-CoV-2 and the researchers found the infection effectively persisted for up to 28 days. Most interesting, however, were the experiments with only mild or moderate viral exposures. In these cases, the researchers saw cardiac function recover from any initial abnormalities within a month. But the virus remained present in the heart tissue despite causing any observable dysfunction.

“The relationship between the severity of acute illness and persistent viral infection in the heart tissue is indirectly suggested by experiments conducted in the paper using various viral titers,” explain Masumoto and Murata in an email to New Atlas. “In other words, if exposed to a very high viral load during the acute phase, it may lead to fatal acute cardiac infection rather than persistent infection. Conversely, infection with a milder viral load may result in the virus lingering in the heart without causing heart dysfunction, indicating the potential for persistent infection.”

Then, to mimic what happens in a human heart in cases of acute ischemic heart disease, the researchers exposed their cardiac model to hypoxic stress. This simulates a scenario where heart tissue struggles to meet increased oxygen demands.

The experiments found heart tissue with a persistent SARS-CoV-2 infection showed significantly increased dysfunction when exposed to stress compared to uninfected cardiac models. This was despite the infection being so mild that there was no identifiable day-to-day dysfunction.

“Our findings suggest that patients with persistent SARS-CoV-2 infection may be more susceptible to developing heart dysfunction compared to non-infected individuals in the face of these increasingly prevalent diseases,” Masumoto and Murata say. “Ischemic heart diseases fundamentally arise from an imbalance between oxygen demand and supply to the heart. Therefore, situations where oxygen demand in the heart increases rapidly, such as excessive exercise, might potentially create similar stress conditions on the heart.”

It’s important to note that there are many unanswered questions right now. It is only speculation to suggest this lab model of persistent SARS-CoV-2 infection in heart tissue is responsible for the noted real-world increases in cardiac events following COVID. It is also unclear how often infections lead to persistent infiltration of heart tissue. Does vaccination reduce one’s likelihood of a persistent infection? Do we all have some trace of SARS-CoV-2 in our heart tissue now, or is it just some of us? And perhaps most significantly, do frequent reinfections increase the chances of a persistent infection in heart tissue?

Masumoto and Murata call their findings a “warning for the possibility of a heart failure pandemic in the post COVID-19 era.” They are also cautious of not being unnecessarily alarmist. They suggest these potential heart health issues can be mitigated if we work now to recognize and understand what is possibly happening.

“We’re not suggesting an undue fear of SARS-CoV-2 in our research,” Masumoto and Murata add. “Rather, we propose coexistence with SARS-CoV-2 in the post-COVID-19 era. We hope that our research results will advance the development of diagnostic and treatment methods for persistent cardiac infection, enabling coexistence between the novel coronavirus and humanity.”

So what now? If the 1918 flu pandemic caused a noticeable spike in heart disease over the following 50 years then what could a virus with a greater propensity for heart infiltration like SARS-CoV-2 cause?

There are too many unknowns to truly understand what the long-term effects of the COVID pandemic will be. And realistically, we will only clearly know decades from now if a few bouts with SARS-CoV-2 in 2020 and 2021 can lead to increased chances of heart disease in later life.

But we do know some things for sure. We know that viral infections can play a role in the development of heart disease. We also know that SARS-CoV-2 can affect the heart in ways that are relatively unique to coronaviruses. And we certainly know that over the first few years of the pandemic there has been a distinct increase in fatal cardiac events.

There are also some things we don’t know for sure but have suspicions about. It is possible the 1918 flu pandemic triggered a century of poor health outcomes in its survivors. It is also possible the SARS-CoV-2 virus can lead to latent infections in the heart.

Eileen Crimmins, an demography expert and professor at USC Leonard Davis School of Gerontology, is clear in stating the possible long-term concerns of this COVID pandemic.

“I think that COVID is setting us up for a hundred years of problems.”