Cardiologists making strides in COVID-19 research
COVID-19 is predominantly considered an infectious and respiratory disease, but it is intertwined with the CV system as well. That means cardiologists have a lot to contribute to battle it, especially in the area of pathophysiology.
Because COVID-19 is often considered an ICU issue and an infectious disease, cardiologists have at times been left on the sideline during the pandemic. But we now know that there are many CV implications of COVID-19. There have been cases of myocarditis, although not as many as initially thought. There are many patients with elevation of biomarkers of cardiomyocyte injury (high-sensitivity cardiac troponin T or I). There have been a lot of cases of right HF, often from pulmonary embolism and many with thrombophlebitis.
We have learned that the pathways that lead to HF and even CAD — the inflammatory pathways and the cytokine pathways that produce HF — are some of the same pathways that we see in COVID-19. This is an aspect of the disease that is not discussed in infectious disease or pulmonary journals. The challenge for cardiologists is to get out that science and make an impact.
Machine learning and biomarkers
To that end, I am part of a group of cardiologists from around the world that early in the pandemic began to meet — virtually, of course — regularly to communicate about what we were seeing regarding the impact of the pandemic in our respective regions, and about what research projects we might be able to undertake to prevent and treat COVID-19. This led to the formation of the Evermore Medical Foundation to provide a more formalized structure for such efforts. We hope to compile research into a large database that we can all use and that will enable us to save some blood samples. We would also like to fund some COVID-19 long-hauler multidisciplinary clinics, a series of webinars around the world and some fellowships so people can learn to study how to battle this disease.
Much of the emphasis has been on machine learning and biomarkers. Biomarkers can establish who is going to get sick or die of COVID-19, and maybe who might need what treatment. Biomarkers are very sensitive but not specific, but machine learning can make them more specific.
Repurposing inexpensive drugs
The group decided early on to try to repurpose older inexpensive drugs that can be used in developing nations or where other therapies are not available. Unfortunately, there are not really any drugs available for this worldwide. Developing new drugs takes hundreds of millions of dollars and if they ever are approved, they will be so expensive that people from developing nations will not be able to afford them. These same countries are not going to be able to get vaccinations very quickly, either.
From the beginning, the one old drug that stood out was spironolactone, a mineralocorticoid receptor antagonist.
Bertram Pitt, MD, emeritus professor of medicine at the University of Michigan School of Medicine, suggested that mineralocorticoid receptor antagonists have been shown to increase ACE2 in the lungs in patients with HF, and therefore could decrease pulmonary fibrosis and improve lung diffusion. Spironolactone is a good candidate due to its off-target anti-androgenic effects resulting in suppression of the transmembrane serine protease 2 (TMPRSS2) activity that is mandatory for SARS-CoV-2 cell entry.
Simon Matskeplishvilli, MD, senior scientist at the Lomonosov Moscow State University Medical Center and a member of the Russian Academy of Sciences, observed a decrease in lung fibrosis in hospitalized patients with severe COVID-19 treated with spironolactone. An example can be seen in Figure 1.
A randomized clinical trial with the combination of spironolactone and dipyridamole, which appears to add antifibrotic and antithrombotic effects, is now underway. Combining them may produce an anticoagulant effect without excess bleeding risk. Both drugs have an excellent safety profile and if proven effective could provide an important input in treatment of COVID-19 in different clinical settings, including massive outbreaks during second and third waves of infection. An outline of the trial protocol can be seen in Figure 2.
Another drug with potential is low-dose naloxone. It comes into the same pathways, virtually without symptoms. Also being evaluated are colchicine and valproic acid, among others. All these appear to have good side effect profiles. We are fortunate to be able to do these studies in six to eight countries, and we have been in contact with pharmaceutical companies that said they will compound and distribute these drugs if our studies are successful.
There are many opportunities for research into “long-hauler syndrome” — CV and other conditions that develop long after an individual has had COVID-19.
One potentially fertile area is in something we call post-COVID tachycardia syndrome. Some patients, even those who never knew they had COVID-19 until they received a positive antibody test from their physician, notice that their pulse rate is elevated and they are having palpitations. At times they may feel weak or as if they are going to pass out. There is a condition called postural orthostatic tachycardia syndrome (POTS), a non-COVID-19-related tachycardia with autonomic dysfunction. COVID-19 can bring about something like that, but in a lot of the patients we have seen so far, they do not have POTS per se; their heart rate can go up any time of the day, not just when they stand up or when their BP declines.
The Karolinska Institute in Stockholm is world-renowned for treating POTS, and Marcus Ståhlberg, MD, PhD, professor of cardiology from Karolinska University Hospital, is seeing this POTS-like condition in patients who had COVID-19. Like POTS, it occurs mostly in women, often in those who did not have many symptoms, or any at all. As with many conditions that affect predominantly women, patients with it were often being ignored. These symptoms can ruin one’s life, as activity may be impossible without having one’s heart race or even passing out.
Data from these patients suggest that sinus tachycardia is involved in the pathophysiology in long-haulers and may constitute a therapeutic target for symptom relief and improved quality of life. A paper defining post-COVID tachycardia syndrome is in the works, as is a registry. A number of potential treatments for the syndrome will be evaluated, including ivabradine, which is known to decrease tachycardia and is now generic, and low-dose naloxone. The POCAHONTAS study of ivabradine and possibly other drugs and combinations will begin enrollment soon. We know that ivabradine can reduce orthostatic heart rate increase and improve orthostatic tolerance in patients with POTS without COVID-19. If ivabradine has the same salutary effects in COVID-19-associated POTS and/or other types of long-hauler syndromes involving sinus tachycardia, that could make a tremendous difference for those patients.
Another notable characteristic of COVID-19 long-haulers is that they complain of weakness and lack of energy. There are questions about whether this is low output syndrome, a low-grade myocarditis, progressive left ventricular dysfunction or something else. These patients have elevations in troponin, B-type natriuretic peptide and other biomarkers. This suggests there may be some ongoing cardiac inflammatory activation and maybe cytokine activation. We need to define the problem, and once we do, then we can think about treatments.
PE, to the extent that it may cause right HF, is another problem that has been reported in COVID-19 long-haulers, and requires different medications from traditional HF therapies. We have noticed that D-dimer levels are very high in patients with COVID-19, as they are in patients with PE, so we may be able to apply our experience with PE treatments to these patients. We have been collecting biomarkers, including D-dimer, B-type natriuretic peptide and interleukin, from patients during their hospital stays, and the data on changes in these biomarkers may be helpful.
Research in these areas is valuable because when there are more surges, we can be prepared, with the help of machine learning, to identify who is at risk for conditions such as myocarditis or PE and to treat patients who develop CV issues with the therapies that have been studied. For long-haulers, we may be able to develop some machine learning algorithms that can predict when these patients can get out of the hospital, or predict who may be at great risk later on.
Efforts are underway to learn more about vaccines around the world.
Projects under consideration include:
- Is there a difference in responses to different vaccines based on sex/gender and race? On previous COVID-19 infection? On premorbid conditions such as obesity, diabetes and hypertension?
- What is the efficacy of different vaccines on various COVID-19 variants such as B.1.351?
- Can we develop machine learning algorithms to determine the best timing of a second vaccine?
- Are there circumstances where a second vaccine need not be given?
- What is the risk of a nonvaccinated household member to be infected by someone who is vaccinated?
We have already found out from the Russian database that people who had previous pneumococcal influenza vaccine had about a 50% less chance of getting COVID-19 infection.
Humberto Villacorta, MD, PhD, professor of cardiology at Fluminense Federal University in Niteroi, Brazil, found that rates of symptomatic COVID-19 infection were more than 50% lower and rates of hospitalization for COVID-19 were almost 75% lower in people who received the measles, mumps and rubella vaccine beforehand. What we suggest is that there is a heterologous protective immunity of some other vaccines. Immo Weichert, MRCP, acute physician at Ipswich Hospital NHS Trust, U.K., is putting together a study on this topic. Mass vaccination may not be feasible in all countries, and the efficacy of existing vaccines against current and future variants is not well defined, so “priming” the immune system with other vaccines may be a worthwhile strategy.
Therefore, we are looking at the possibility of putting other vaccinations such as the influenza and measles, mumps and rubella vaccines, which are easily available and almost free, together into a “vaccination bomb.”
Messages for practitioners
For cardiologists in clinical practice, nothing is more important than to have your patients get vaccinated, keep their distance from others and wear a mask. The medical community also needs to keep in mind that many people will contract COVID-19 but never know they have it at the time. These people can succumb to some of the COVID long-hauler symptoms later. These symptoms could be 10 times worse after than they ever were during when the patient had the virus. We need to be aware of this group and study those patients. There is a whole lot of work for cardiologists and other medical practitioners to do in the fight against COVID-19.
- Mareev VY, et al. Kardiologiia. 2020;doi:10.18087/cardio.2020.9.n1338.
- For more information:
- Alan S. Maisel, MD, is emeritus professor of medicine at the University of California, San Diego, and a co-founder of the Evermore Medical Foundation. He can be reached at firstname.lastname@example.org.