Strokes are the third leading cause of death in the United States. 800,000 people suffer a stroke every year, and the consequences are frequently devastating. Lives are not just lost, but changed forever – speech permanently silenced, arms and legs turned into useless appendages. The brain is very expensive real estate and it is little surprise that a clot the size of a pinhead lodged in a blood vessel feeding the brain is all that is needed to wreak a devastation most fear worse than death.
Most of the time the source of the debris that results in a stroke can be readily identified, but at least one-third of the time no source can be found. These have been termed cryptogenic strokes by the medical community mostly because it is an intelligent sounding phrase when your doctor does not know why something happened. Almost 30% of strokes in patients under the age of 55 are found to be cryptogenic. Until the mid 80’s there was little progress in identifying the cause of these strokes, but around the same time I was wondering why Duran Duran was running through jungles in Sri Lanka on MTV, cardiologists began injecting air into the heart to shed light on this mystery.
Understanding why watching bubbles travel through the heart was of such interest to cardiologists relies on understanding that the heart and vascular system is a house divided. The four chambers of the heart are divided between de-oxygenated blood on the right side of the heart, and oxygenated blood on the left side of the heart. Veins carry deoxygenated blood from the major organs back to the right side of the heart, and the right heart pumps blood to the lungs to be oxygenated. A rare group of patients, however, tell us that the lungs serve as more than just an oxygenation chamber. Ordinarily arteries and veins connect in thin capillary beds in the lungs that are narrow enough to only allow one red blood cell to pass at a time (Fig. 1A). This is not the case in patients with arterio-venous malformations in whom arteries and veins instead meet in a grotesque collection of dilated, misshapen vessels. (Fig. 1B, 1C).
Figure 1. A. Normal capillary bed B, C. arteriovenous malformation
And just like that, a simple alteration of the capillary bed akin to replacing a small country road with a four lane highway increases the risk of brain abscesses by 500 times and the risk of strokes 10-30 times.
Figure 2. B. Relative risk of brain abscess compared to normal D. Relative risk of stroke compared to normal
This suggested that the lungs also serve as an important final filter for blood seeking passage from the right sided venous circulation to the left sided arterial circulation. Macrophages – cells that recognize and eat bacteria – line the thin walled capillaries of the lung, screening all the blood that passes and functioning to ‘purify’ the blood of bacteria. Narrowing passageways to a single file of cells also creates a physical barrier preventing blood clots from entering the left side of the heart. A pin head sized thrombus is of little consequence in the lungs, but is catastrophic in the brain. Thus the lungs can be thought of as an important final filter protecting the left sided circulation from pathogenic organisms and thrombi.
There is another conduit that allows blood to bypass the ‘lung filter’ that has nothing to do with the lungs. This is a connection that exists within the heart that is necessary for fetal circulation. Fetal circulation relies on bypassing the relatively useless in-utero fluid filled fetal lungs so that oxygenated blood can pass directly from the right heart into the left heart via an interruption between the upper chambers of the heart known as the foramen ovale. This interruption closes in most during the first days after birth, but remains open in 25% and is known as a patent foramen ovale (figure 3).
Figure 3. The Patent Foramen Ovale
As imaging of the heart with ultrasound progressed, cardiologists started to report on a very troubling finding – clots were seen to actually be passing from the right sided circulation into the left sided circulation through a patent foramen ovale. (Video 1) The subsequent finding that almost 40% of patients with no identifiable cause of stroke had a PFO seemed to lend credence to the notion that the PFO lay at the heart of the mystery of patients with cryptogenic strokes. The PFO, it was posited was the conduit that allowed clots from the right sided circulation to travel into the left side of the heart and be pumped into the brain to cause a stroke.
Video 1. Serpiginous thrombus in transit through patent foramen ovale.
Faced with patients who had already suffered one cryptogenic stroke, cardiologists began closing PFOs using a minimally invasive percutaneous approach. (Video 2)
Video 2. Animation of a PFO closure
The FDA did not have the data to approve the device initially, and so the device was used under the FDA’s Humanitarian Device Exemption program while randomized controlled trials were started by device companies.
Three randomized control trials of percutaneous closure device vs. medical therapy were undertaken, and to some people’s surprise, the overall trial result was negative. Recently, the American Academy of Neurology (AAN) weighed in and released a panel recommendation that reviewed the available evidence and concluded that ‘clinicians should not routinely offer percutaneous PFO closure to patients with cryptogenic ischemic strokes outside of a research setting’. Panelists essentially pooled data from the 3 randomized control trials to arrive at their conclusions. Their analysis may be statistically pure, but I found it to a simple treatment of what is a complex issue.
The subsequent post takes a deep dive into the randomized control trials of the closure device.
Anish Koka is a cardiologist who unfortunately sees a lot of patients with strokes. He has no financial conflicts of interest related to PFO closure devices. He can be reached on Twitter @anish_koka