Why is tricuspid valve endocarditis more common in persons who inject drugs?
On this episode of the podcast, we continue the discussion of valvular heart disease, moving from the left heart to the right heart. In Episode 65, we talked about the curious predilection of rheumatic heart disease for the mitral valve. On this episode, we ask: why is tricuspid valve endocarditis more common in persons who inject drugs?
One study from Spain examined 1529 episodes of infective endocarditis in persons who inject drugs (PWID). The cohort spanned more than 15 years, from 1977–1993. The tricuspid valve was involved in 68% of cases, followed by the aortic in 7%, the mitral in 5%, and the pulmonic valve in just 1% of cases. Other cohort studies similarly show that the tricuspid valve is involved more frequently in this setting than in those without a history of intravenous drug use (IVDU).
Looking at those without a reported history of intravenous drug use, a 2009 study in the Archives of Internal Medicine looked at 2781 patients with infective endocarditis and reported mitral valve involvement in 41%, aortic in 38%, tricuspid in 12%, and pulmonic in, again, just 1%. A 2020 JAAC study specifically compared PWID and those who do not inject drugs. A total of 7,616 patients were included. In PWID, the tricuspid valve was involved in 56% of cases, compared with just 18% in those without a history of IVDU.
Collectively, these data make clear that in infectious endocarditis, tricuspid involvement is far higher in PWID than in those without this history.
In order to understand the initial question of why the tricuspid valve is more commonly affected in PWID, it is essential to first understand the pathogenesis of infective endocarditis in general. In doing so, we’ll cover why left-sided is more common overall. At least three steps are required for infective endocarditis to occur. First, there needs to be valvular endothelial injury. Second, thrombus forms at the site of injury. Third and finally, bacteria seed this thrombus, causing endocarditis.
For step one, the key observation is that vegetations rarely form on an intact endothelium. In the 1960s and 70s, a series of experiments were performed by Penelope Garrison, Lawrence Freedman, and David Durack. They involved the use of polyethylene catheters acting as disruptors of the endothelium on the heart valves of rabbits. In some rabbits, they would insert these catheters into the hearts, causing trauma to the valves. In others, they wouldn’t. In all animals, they would then inject bacteria into the blood. Only those with endothelial injury developed infective endocarditis.
Clearly, people don’t routinely have their valves poked with catheters. Instead, the trauma causing endothelial injury results from high pressures and velocities. In 1963 Simon Robard published a set of experiments using Venturi tubes to model flow across valves. Recall that Venturi tubes are shaped like an hourglass and contain an area of constriction that varies the flow. Robard injected a bacterial aerosol into the air stream passing through one of these Venturi tubes. He showed that high pressure drives an infected fluid to a low-pressure sink and that this creates the characteristic pattern of bacterial colony distribution in endocarditis. The thought is that high velocity and turbulence created when blood flows from high to low pressure across a narrow orifice traumatizes and injures the endothelial surface. Across the aortic valve, the low-pressure sink is on the ventricular side. Across the mitral valve, the low-pressure sink is on the atrial side.
This explains why most vegetations are on the ventricular side of the aortic valve and the atrial side of the mitral valve. These are the lower-pressure sinks through which blood flows from areas of higher pressure. But this means you will typically have some regurgitant flow to see this injury happen. Similar hemodynamic relations are seen with tricuspid valve endocarditis and infections related to coarctation of the aorta and patent ductus arteriosus.
This also helps explain the rarity of pulmonic valve endocarditis. The pressures around this valve and the gradient across it may not be high enough to generate the turbulent flow required for endothelial injury. This is probably one of many factors at play.
The second step in the formation of infective endocarditis is the generation of thrombi consisting of platelets interwoven with strands of fibrin begin to form. These develop at the sites of endothelial injury and are what bacteria infect if one develops infectious endocarditis. And that, of course, is the third step.
It should note there that Staph aureus may be unique in its ability to cause endocarditis without the first two steps. It seems to be able to affect normal heart valve tissue. But, most cases of endocarditis, even those caused by Staph aureus, still require these first two steps.
One question that emerges from these mechanisms is whether antithrombotic therapies might prevent endocarditis. We’ve known about the role of endothelial injury and microthrombi since at least the 1930s. And the first human studies of heparin were also in the 1930s and that penicillin wasn’t introduced until 1941. So, there was a lot of enthusiasm for the use of heparin AFTER the diagnosis of endocarditis in the late 1930 and early 1940. We didn’t have other great therapies available. Unfortunately, these trials were basically negative.
It, of course, makes more sense that antithrombotic medications would be more effective as preventative agents. Endocarditis is too rare to do a prospective randomized trial. One would need to enroll way too many people to see an effect size. But there are animal studies where they give antiplatelets and anticoagulants than attempt to provoke endocarditis. For example, a 2015 study published in the Journal of Infectious Disease looked at a rat model of experimental endocarditis following prolonged low-grade bacteremia. Prophylaxis with antiplatelets like aspirin or anticoagulants like dabigatran were started two days before inoculation with Streptococcus gordonii or Staphylococcus aureus. The combination of aspirin plus ticlopidine protected 21% of rats from S. gordonii endocarditis and 55% of rats from S. aureus endocarditis.
Human data are lacking so, unsurprisingly, the use of antiplatelets and/or anticoagulants for the prevention or treatment is not recommended.
Turning back to the original question of why IVDU affects the tricuspid valve so often, multiple factors are at play, but endothelial injury to the tricuspid valve is likely key. Particularly as you think about the pathogenesis of endocarditis of the left heart. The question then becomes: what causes this injury in the setting of IVDU?
The leading theory is that particulate matter entering with the injected material leads to repeated injury to the tricuspid valve. This is a scenario where it’s being the first valve accessed probably does play a role.
As to why this particulate matter also leads to endothelial injury on the left side as well, it likely relates to filtering by the lungs. The diameter of pulmonary capillaries is about 6 μm “protecting” the aortic and mitral valves from endothelial injury induced by larger particles typically injected.
Other factors play a role. For example, one difference may relate to the organisms involved. S. aureus is the most common cause of endocarditis in people who inject drugs. As noted earlier, S. aureus has a greater ability to affect normal valves.
There is at least one other condition that oddly favors right-sided valves over left-sided valves: carcinoid syndrome. Here the left/right difference is more stark. In one study of carcinoid heart, 97% had tricuspid valve involvement, with just 7% mitral and 3% aortic.
And the pulmonic valve was involved in 88% of cases! This demonstrates well the difference in pathophysiology. In carcinoid syndrome, the underlying valve architecture is not disrupted. Because the initial endothelial injury isn’t required for carcinoid plaque formation it can happen on the pulmonic valve.
The aortic and mitral valves are relatively spared in carcinoid heart. Why? Serotonin, which likely has a key pathogenic role, is inactivated by the lungs. In fact, of the five patients with left-heart involvement in the study mentioned above, four had a patent foramen ovale or lung involvement, allowing serotonin to bypass this filter.
Take Home Points
- Infective endocarditis more commonly affects the high-pressure mitral and aortic valves as this predisposes to endothelial injury.
- For persons who inject drugs, particulate matter leads to tricuspid valve injury.
- The lungs probably filter much of the particulate matter, thereby providing some protection to the aortic and mitral valves.
CME/MOC
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Credits & Citation
◾️Episode and show notes written by Tony Breu
◾️Audio edited by Clair Morgan of nodderly.com
Breu AC, Cooper AZ, Abrams HR. More Right Than Left. The Curious Clinicians Podcast. March 8, 2023.
Image credit: https://pubmed.ncbi.nlm.nih.gov/13974594/
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