As a radiologist, this is my coffee-mug aphorism for the epistemology of medical imaging. It reminds me that the picture or the test result is not the patient or even the disease.
Here is one of the hierarchies I use when thinking about coronary disease. It's a rough ordering from top to bottom of how far away you are from "the thing itself" when looking for evidence of a previous myocardial infarct.
From useless to definitive:
Framingham risk score - modern blood tests ( HDL , LDL-P, oxidized LDL, etc.)
Calcium score (Heart scan for coronary calcium)
Intravascular Coronary Ultrasound
Abnormal coronary angiogram
Abnormal coronary CTA
EKG evidence of infarct
Stress SPECT Nuclear Medicine perfusion
Cardiac perfusion MRI with dobutamine
Late Gadolinium enhancement cardiac MRI (LGE)
Death with autopsy evidence of MI.
I have ordered these roughly according to how definitive they are in establishing myocardial injury - whether you have actually had a heart attack sometime in the past (not acutely, as that can often be shown with serum enzymes).
Think of Lindeberg's studies of the Kitavans. He used EKGs (electrocardiograms) to look for evidence of prior MI (myocardial infarct or heart attack). Comparing to the known prevalence of EKG abnormalities in western subjects, he concluded that there was no evidence of heart disease in Kitava.
The Kitavans are fascinating because they have high carb consumption and appear to be much healthier than those on the SAD - the standard american diet. They also have some "paradoxical" lipid markers that (rightfully) call into question the very idea that the lipid markers that cardiologists love to measure mean anything outside the context of a particular diet. In my opinion, they help cast doubt on the very idea that either good or bad blood lipids "cause" anything. Rather, they are just markers for the diet - the diet effects the actual changes.
EKG is not that sensitive and can be often be false positive.
What if we wanted the most definitive evidence that we could get, short of sacrificing our poor subjects in the interest of science and having a pathologist look at their hearts?
How about invasive coronary angiograms? Unfortunately, a conventional angiogram only shows stenosis or narrowing of the coronary arteries and does not show a heart attack unless there is gross wall motion abnormality, and that is an indirect sign anyway.
How about a nuclear medicine stress test? - this 20-year-old procedure is the most traditional non-invasive way to look for heart disease - unfortunately it also requires a fairly large infarcted (damaged) area to reliably detect if there has ever been a heart attack. If looking just for physiologic evidence of stenosis, it requires a 75% or greater arterial narrowing to reliably detect disease. It is not very sensitive.
It would surprise even a lot of my fellow physicians to know that the most sensitive way to tell if there is any coronary atherosclerosis whatsoever is not nuclear medicine or an invasive coronary angiogram - it is CCTA or coronary CTA.
CCTA is not "calcium scoring" (I avoid calling calcium scoring a "heart scan" as at my center there are a half-dozen procedures that could be called that). CCTA is a CT scan done with a 64- slice multi-detector CT scanner that rotates fast enough to image the coronary arteries. Although the spatial resolution is not as high as conventional catheter angiography, CCTA can directly image early "soft" plaque that is totally invisible on conventional angiography or on simple calcium scoring. The only test that is better - the absolute gold standard for detection of coronary plaque in the living - is called intravascular ultrasound or IVUS. But IVUS requires invasive insertion of an ultrasound probe into the coronary arteries in a procedure similar to conventional angiography. It is mainly a research tool. Not so good for screening asymptomatic subjects.
So to detect any atherosclerosis of the coronary arteries in a population, the best practical test would be CCTA.
But what if we wanted to know, with as great a degree of certainty as possible without waiting for the death of our subjects, whether they had ever had a heart attack or any damage to the heart muscle? After all, the important thing is if you have an actual heart attack or die - that is "the thing itself" in this case.
Then the choice would be cardiac MRI with late gadolinium enhancement or LGE.
Here is how LGE works. When heart muscle is damaged, there are pathologic changes in the tissue that we characterize, in our highly precise way as medical scientists, as "scar tissue". This scar tissue will have a pattern of blood pooling or stasis, where, unlike normal heart muscle, the blood seeps in slowly, and then does not wash out as fast with time.
LGE exploits this phenomenon. We give an agent intravenously that shows up bright on MRI images called gadolinium or Gd (It's actually a compound or chelate as pure Gadolinium is poisonous).
Firstly, we can first get heart images during the early part of the Gd administration and use this to look for ischemia or temporary insufficiency of blood flow with stress. (This is a good way to tell if there is a narrowing of one of the arteries supplying the heart - the coronary arteries - and is similar to the mechanism used in a nuclear medicine stress test - only much more sensitive.) Then we get delayed images. On these delayed images, normal heart muscle will return to its non- bright appearance, but the scar or damaged heart muscle will stay bright. The important thing to know is that we can detect such areas with much higher resolution than nuclear medicine techniques, and we can see non- transmural (less severe -not all the way through the heart wall) infarcts and infarcts so small they have no effect on wall motion.
This LGE technique has been validated with animal and human pathologic studies. It truly is the best way other than autopsy to tell if there has been permanent damage to the heart muscle.
Mainstream thinking still maintains that lots of sustained aerobic exercise is good for cardiovascular health - to the point where everyone uses the word "cardio" as a synonym for long sessions of aerobic effort. Like the diet-heart and lipid hypotheses, this idea is actually only about 40 years old. In the first half of the 20th century, it would have been thought as absurd as the idea that butter clogs your arteries.
So let's say you want to see just how protective "cardio" is against the number one killer of Americans -coronary heart disease. Instead of just looking for atherosclerosis, though, we want "the thing itself" of actual myocardial damage. Who knows, maybe runners get more plaque but have fewer plaque ruptures or a less thrombogenic blood profile?
So in the Breuckmann study, they recruited 102 active marathon runners. To be a marathon runner (and perhaps to maximize their power to show how healthy "cardio" is) required at least 5 marathons in the past 3 years. Many had run dozens or more in their lifetime. Anyone with a known history of heart disease or diabetes was excluded. The average age was 57 with age 50-72. The median number of marathons was 20. Weekly mileage was 35 (55km). Mean work was 4700 METs per week.
There were 102 totally asymptomatic age-matched controls, also with no history of diabetes, who had no significant history of vigorous exercise.
All subjects had cardiac MRI with LGE imaging. Those with LGE abnormalities were called back to have perfusion imaging as well to help tell if they had evidence for ischemia (which might indicate narrowing of a coronary artery).
Sidebar: Ischemia means temporary and reversible changes in oxygenation of tissue. Infarction means ischemia has occurred to the point that tissue has died and this is irreversible. LGE means irreversible loss of tissue or infarction.
What do you think they found? After all, these were a bunch of completely asymptomatic runners.
Would you believe 12% of asymptomatic marathon runners had evidence of myocardial damage on LGE?
Would you believe that among the sedentary age matched controls only 4% had abnormal LGE?
I am obliged to point out that by the conventional arbitrary criterion used in biomedical publishing, the difference was "not statistically significant". To meet the standard definition, there would have to be a 5% or less chance of a difference in rate as extreme as what was found, given that there is no difference between the groups. Instead, the significance level was 8% by McNemar's test, so there is only an 8% probability of a result as extreme as what was obtained, assuming the null hypothesis is true (that there is no difference).
Sidebar: Does anyone else think it's strange that if your doctor said "you have only an 8% chance you have disease" you would find that reassuring, but we are supposed to be unsatisfied with an 8% probability of obtaining our result if there is no difference? Stop doing what you are told and read the statistics without letting the authors or editors tell you what is "significant". Yes, P = .00001 is better than .05. But you can decide for yourself, it is not written in stone.
Let's take a closer look at the results.
Among runners with LGE, there were two patterns of abnormality. In the first pattern, found in 5, there was evidence on perfusion imaging and an anatomic pattern that confirmed these were typical ischemic infarcts. That is, they are evidence of heart attacks due to insufficient blood supply in the distribution of a particular diseased coronary artery. The kind of heart attacks we are all familiar with that kill 500,000 Americans a year. Two of the controls had these classic appearing infarcts.
Runners 5 classic heart attacks
Sedentary 2 classic heart attacks
The second pattern of abnormality, seen in 7 runners and 2 of the sedentary, was non-classic LGE. These areas of dead tissue were found in the middle or outer layers of the heart muscle, rather than the subendocardial layer. They also tended to be more patchy in distribution. This non-classical pattern can indicate scarring or fibrosis from non-ischemic injury to the heart muscle, including myocarditis. However, despite lack of evidence for ischemia on perfusion MRI, this pattern can also occur due to coronary microembolization, where a major coronary artery is not narrow enough to cause ischemia, yet small bits of plaque break off or tiny blood clots form and plug the arterioles deep in the muscle - causing infarction and permanent scarring in an "atypical" pattern.
The authors speculate that this atypical infarction could be due to exaggerated shear stress related to marathon running and disturbance of prothrombotic and fibrinolytic systems contributing to microthrombotic emboli.
I think that is a reasonable speculation.
Runners 7 non-classic heart attacks
Sedentary 2 non-classic heart attacks
So whether we are looking at classic heart attacks or non-classic, the ratio is about 2.5 or 3 to 1 in favor of being relatively sedentary.
But, you might say, how do we know this LGE is significant?
First, there was evidence of ischemia in most of the classic cases even if you don't buy my statement LGE by itself is definitive evidence of a heart attack.
Second, in only 21 months of followup, 1 of 90 runners without LGE had a significant coronary event and 3 of 17 runners with LGE had a significant event. Significant events included two cases of collapse and EKG abnormalities after a race - similar to what felled Salazar and probably JIm Fixx. None died, but all were proved to have severe coronary disease by conventional angiography and were stented or had bypass surgery. This difference in event-free survival - 1% vs 18% -was significant by log-rank at the .0001 level.
Third, the median CAC (coronary artery calcium score) in the runners with LGE was 192, and in the runners with no LGE it was 26. This is a big difference and shows that coronary atherosclerosis is tracking the LGE evidence of heart attacks. So it's probably not just thrombogenicity or arrythmias on top of an invariant level of coronary disease.
Now I'll be good and put on my Karl Popper hat for jusr a second. Maybe the runners all took up running a few years ago and had bad coronary artery disease to begin with? Maybe they had not yet run enough marathons to reverse their disease? The rate of former smokers - those who had ever smoked any amount, was around 50% in the marathoners. In the editorial in Radiology accompanying the Brueckman article, some cardiologists speculated that the group may indeed have consisted of more formerly unhealthy people than is usually found among group of runners. But among the controls the former smoking rate was 42%, and the active smoking rate, which would logically correlate with long- term smoking was actually higher. It's hard to see how 25% more former smokers - mostly those who had quite many years ago - could result in 200% more heart damage.
From another good paper by the same group on the same subjects:
1) The more marathons run, the higher the likelihood of heart disease. The number of marathons run was an independent and significant predictor of the likelihood of myocardial damage.
The runners had about the same prevalence of non-zero coronary calcium compared to age matched controls randomly assigned from a survey population. This was so despite the Framingham risk score being lower for the runners and there being more than 5 times as many active smokers among the controls.
2) Compared to age-matched controls, the runners had 40% higher HDL -c (mean of 74 mg/dl) and 18% lower LDL (121) Again, these more favorable lipid risk factors did not show a benefit in calcium scores, which correlate well with atherosclerosis (not heart attack, but coronary heart disease). Statin deficiency, I guess. How many torpedoes before the Bismarck of the Lipid Hypothesis finally sinks?
3) Compared to age and risk factor matched controls (a second set of controls with similar rates of smoking and other risk factors), 36% of runners had a calcium score or CAC above 100, versus 21% of age and risk factor matched controls. (High CAC means more coronary atherosclerosis) In other words, a group with similar risk factors, including smoking history, had much fewer subjects with a high calcium scores - which are a good proxy in populations for coronary disease and risk of death. So if the "risk factors" like lipids and BMI and such really are helping you, running seems to be doing something to undo the effect.
There are many good references quoted by Brueckmann and Mohlenkamp.
Among them is This paper by Kwong and Chan from Circulation. They looked at the presence of LGE as a predictor of major cardiac events (heart attack) and the ultimate relevant end point for us all - death.
"LGE demonstrated the strongest unadjusted associations with MCE and cardiac mortality (hazard ratios of 8.29 and 10.9, respectively; both P 0.0001).
LGE remained the strongest predictor selected in the best overall models for MCE and cardiac mortality."
A hazard ratio of 11 for future cardiac mortality is very, very, high. 1100% more likely to die is a gold standard hazard ratio, of the same magnitude as smoking and lung cancer. This makes it hard to doubt the significance of having LGE and would not likely be seen if there were benign explanations for the presence of LGE.
This makes sense. How could there be a better predictor of whether you will have a heart attack than evidence that you have already had a clinically silent one?
Brueckmann and Mohlenkamp are German, but get points for an English level of understatement:
"...It seems safe to state that marathon runners most likely did not have a lower rate of LGE than did the healthy control subjects, who did not regularly exercise."
Do you think that might be why this paper was in Radiology instead of JAMA or NEJM? Is that why there was no press conference before the paper came out?
It's time for some Kuhnian iconoclasm. Let's take the hammer to some "normal science".
I think that atherosclerosis is not caused by lack of sustained high-level aerobic ("cardio") exercise.
Just like I don't think lack of "cardio" is the cause of the obesity epidemic.
I think premature atherosclerois is mostly caused by diet. Our susceptibility to a bad diet is contributed to by genetics.
I think that not only does sustained "cardio" not protect you from atherosclerosis, I think it is quite likely that through repetitive shear stress with endothelial damage and promotion of an inflammatory state, that it may promote atherosclerosis and/or direct cardiac muscle damage.
Further, I think that excessive "cardio" might precipitate the thromboembolic and acute inflammatory events like plaque rupture - acute heart attacks, even if it does not directly contribute to atherosclerosis, which I think it does.
Could "cardio" promote atherosclerosis and myocardial damage by being confounded by diet? That is, could the wheat, excess sugar and linoleic acid found in low fat "healthy" diets be more prevalent in marathon runners by virtue of their greater caloric intake of this noxious garbage?
That's a possibility. I think it may apply to cyclists, most of whom seem to eat horribly and who seem to be prone to osteoporosis.
Even if these findings are all confounded by a noxious athletic diet, I still find no grounds at all to believe that high levels of "cardio" protects your heart or makes you live longer. Certainly not "the more the better" which is what we've been led to think since the 1970s running craze.
I think a modicum of repetitive, aerobic-type physical activity can definitely improve your mood. I like to a run about 5 k a few times a week. It feels good and cross-country seems good for your coordination with all the varied terrain. A little cross-country and some sprinting sure seems to make me more functional.
I am not under the delusion that it will dramatically improve my overall health or my longevity, though. And I've seen no evidence that doing it every day or doing 5 times the mileage would be better. Just the opposite, in fact.
Same goes for eating "fruits and vegetables", gorilla levels of fiber, "antioxidants", and most supplements. No magic foods.
The really good kind of exercise, resistance training, makes you more functional and stronger. That is the only sensible definition of fitness if we follow the hippocratic oath with our selves.
Primum Non Nocere
I vote we keep the terminology. We should keep calling marathons, centuries on the bicycle and hours on those ridiculous stairmasters and treadmills "cardio" to remind us which organ we may be putting at risk.
Running a marathon is starting to look about as smart as boxing or playing football.
Myocardial late gadolinium enhancement: prevalence, pattern, and prognostic relevance in marathon runners.
Running: the risk of coronary events
Impact of Unrecognized Myocardial Scar Detected by Cardiac Magnetic Resonance Imaging on Event-Free Survival in Patients Presenting With Signs or Symptoms of Coronary Artery Disease
Alberto Salazar image by Olivia Bucks of the Oregonian.
The only difference between Salazar and Jim Fixx, is that when Salazar experienced sudden cardiac death due to myocardial infarct from an 80% stenosis of his right coronary artery at age 48, someone showed up with a defibrillator to get his heart re-started. Salazar was a world class marathoner who trained about 30 miles a week at an easy 7:30 pace.
See paleonu.com for more. You can also read some interesting discussion in the comment thread.