Thursday, March 29, 2018

Just In Time? Too Late?

The main results from Howden et al., the paper that inspired this blog post. Middle-aged participants who engaged in aerobic training improved VO2max and left ventricular end-diastolic volume, both markers for reduced incidence of heart disease, whereas participants who engaged in flexibility and strength training did not.

Between ages 21 and 56, my level of exercise was inadequate to non-existent. For a few years thereafter, I went from exercise plan to exercise plan trying to get something to stick, until age 61, when I finally restarted cycling on a regular basis, an exercise program which I have maintained fairly well for almost eight years. Thus, a link on Facebook to an article on BBC News with the title of "Middle-aged can reverse heart risk with exercise, study suggests" had its desired effect: it caught my eye and I clicked through and read the article. Reading the article left me concerned: "...the aerobic exercise regimen should be started before the age of 65 when the heart appears to retain 'plasticity' and the ability to remodel itself." Had I waited too long to restart exercising, or had I managed to just squeak under the wire? Could I really believe any of this anyway? As I have blogged here many times, when encountering an article in the popular press on a scientific study, it is important to go back to the original article from a professional, peer-reviewed journal to make sure that its results were accurately reported, and then to evaluate the study described therein to make sure its conclusions are adequately supported, and that I did. I read the original article and determined that it only investigated people between the ages of 51 and 55. The statement that starting exercise later is is less valuable is in the paper, but it is based on comparing the results in this paper to those in an earlier paper from the same team which investigated people between the ages of 68 and 74. In my discussion of these papers, I will first summarize the claims of the papers, discuss the papers critically, describing their limitations, and finally, I will summarize my "bottom line", what results from these two studies I personally find convincing. (The impatient, who are willing to trust my judgement, should feel free to skip to this Bottom Line.)


Howden et al.1 is the original paper which formed the basis for the article in BBC News. They ask the following question:
"Poor  fitness in middle age is a risk factor for heart failure, particularly heart failure with a preserved ejection fraction. The development of heart failure with a preserved ejection fraction is likely mediated through increased left ventricular (LV) stiffness, a consequence of sedentary aging. In a prospective, parallel group, randomized controlled trial, we examined the effect of 2 years of supervised high- intensity exercise training on LV stiffness."

Fujimoto et al.2 is the earlier paper from the same group. They ask, what is to my eye, a functionally equivalent question:
"Healthy but sedentary aging leads to cardiovascular stiffening, whereas life-long endurance training preserves left ventricular (LV) compliance. However, it is unknown whether exercise training started later in life can reverse the effects of sedentary behavior on the heart." 

The group that published these two papers is a cardiology group. I have no expertise in cardiology so cannot comment critically on this part of their work, I simply have to take the authors at their word. Given that, my understanding of what they are saying is that one form of heart failure is associated with a decrease in left ventricular end-diastolic volume or LVEDV. LVEDV decreases with age, but is higher in the elderly who have exercised their whole lives ("master athletes"). The question both papers are asking is, for one of those unfortunates who have not exercised, does exercise later in life reverse the decrease in LVEDV? The hope is that if exercise can increase LVEDV, this will result in a lower probability of the development of this one kind of heart failure and thus increase longevity.

In addition to LVEDV, the authors of both papers measured a number of other parameters. The one that caught my eye was VO2max, because VO2max is probably the most common biomarker for the beneficial effects of exercise on longevity, one that I have discussed quite often on this blog. The authors barely mentioned their results with VO2max, but I will devote significant attention to them.

The reason for considering Howden et al. and Fujimoto et al. together is the assumption that they did roughly equivalent studies on two age groups and got different results, thus the statement in the BBC News article that exercise after age 65 may be too late to reverse heart damage. There are, however, other differences between the papers that weaken this conclusion. A partial comparison of the two papers is in the next figure:

What we note is that the age groups studied is different and that for the younger age group, LVEDV increases significantly, whereas for the older age group, the difference is not statistically significant. We also note that Howden et al. had many more participants, which by itself will increase the statistical significance of their results, a fact I will discuss in the next section. Finally, we note that VO2max, the workhorse biomarker used in a large number of studies as a proxy for health benefits increased in both studies by similar amounts. (Not shown in the figure is that both increases are statistically significant, P=0.0001 for Howden et al. and P=0.001 for the smaller study reported in Fujimoto et al.)

Another difference between the two studies is that they used different exercise plans:

The first number in each column in the above is the number of rides of this kind done per month. The intensity of the ride is given in the column header. Thus, 15 @ 25 min in the Base Pace column means that 15 rides a month are done at Base Pace, where each ride is 25 minutes long. For Intervals, 3 @ 8 x (30 s "on" 90s "off") means that 3 times a month a ride is done consisting of 8 Intervals, where each interval consists of 30 seconds at Interval Pace followed by 90 seconds at Recovery Pace. Base Pace corresponds to the Heart Rate Zone (HR) 3 and 4 that I use on this blog. MSS corresponds to the boundary between HR 4 and HR 5. The "on" part of the intervals are done in HR 5c. Recovery Pace (ridden during the time between intervals and during a recovery ride done the day after intervals, not shown above) are done in Zones 1 and 2. These HRs are so high, I worry that I have misunderstood the authors, I would find it difficult or impossible to complete the workouts above if this is correct. That said, because of these concerns, I read this part of the papers carefully, and can find no other way to interpret what the authors are saying.

The exercise plan in Fujimoto et al. was one year long as compared to Howden et al. which was two years long, but Howden et al. collected results after ten months and all the benefits of exercise had accrued by then, so I only show the results of this first ten months. Fujimoto et al. described their exercise protocol very clearly, so that it was easy for me to put it into the figure above and I am relatively confident I correctly described it. In contrast, I found the description of the exercise plan in Howden et al. ambiguous and confusing, so I am less confident I have accurately described it.

As noted above, I am not a cardiologist so cannot comment on the protocols used in the two papers to measure cardiac parameters, but to my untrained eye, it seemed that the two papers used different protocols.

Finally, there are differences between the papers that concern parts of the studies not relevant to this blog post. Fujimoto et al. also compared active, age matched (elderly) participants, known as master athletes, to the healthy but sedentary participants in their study, and Howden et al. compared the effects of yoga plus strength training to that of the aerobic training. I am  ignoring these parts of the papers.

Critical Analysis 

The two sentences in Howden et al. that inspired the BBC News article are as follows:
"Epidemiological studies show that a measurement of  fitness in middle age is the strongest predictor of future heart failure. Moreover, in observational studies, the dose of exercise associated with reduced heart failure incidence is much higher than that associated with reduced mortality. However, if exercise is started too late in life (ie, after 65 years) in sedentary individuals, there is little effect on LV stiffness [reference to Fujimoto et al.]"

To my eye, both Howden et al. and Fujimoto et al. seem to be well executed studies and the narrow conclusions that the authors draw from their results seem justified. The focus of my critical analysis will thus focus on the comparison between the two papers, made in Howden et al., that is the basis for the assertion that exercise at age 65 and older to too late to protect against one kind of heart failure.

Before starting, note the narrowness of the assertion: the authors do not deny that exercise for those of us older than 65 can decrease mortality overall, but rather that it may be too late to reduce the incidence of one particular disease. In fact, the VO2max results reported in Fujimoto et al. actively affirm the value of exercise for us old folks. That said, is this narrow assertion supported by the results?

The first reservation comes from the fact that these are biomarker studies. What the authors care about is the effect of exercise on the incidence of one kind of heart failure. What the authors measure is LVEDV. How good is the evidence that reducing LVEDV in late middle age (51 to 55) will result in a reduction in heart failure? Note that just because low LVEDV is associated with heart failure does not demonstrate cause and effect. Howden et al. might, in fact, be in a position to test this hypothesis. If they were to follow the 61 participants in this study, the 28 who did yoga and strength training vs the 33 who did aerobic exercise, and if they found that the aerobic group had a lower incidence of heart failure, this would go a long way towards demonstrating the value of exercise in middle age, but of course that study has not (yet) been done. For now, we must accept uncertainty as the inevitable limitation that result from this being a biomarker study.

Even if we accept that the increase in LVEDV caused by exercise results in a reduction in heart failure, the assertion that age 65 is too late for this benefit is suspect. The basis for this assertion is that no improvement in LVEDV was seen in the older participants of Fujimoto et al., whereas improvement in LVEDV was seen in the relatively younger participants of Howden et al. The problem with this assertion is that there are other explanations for the differences observed between the two papers. Firstly, Holden et al. had many more participants than Fujimoto et al., 33 vs 9. Thus, Holden et al. had much more statistical power. There may have been an increase in LVEDV in the older patients in Fujimoto et al., that was hidden by statistical noise, that would have been seen had they looked at more patients. Secondly, if I am correct that the two papers used different techniques for measuring LVEDV, that could also explain the differences. Finally, and most relevant to this blog, the difference between the two papers could be due to different exercise protocols. A lot of the papers I cover here are about precisely that, which exercise protocol produces the the greatest benefit?

Because this is an exercise blog, I'd like to spend a bit more time on the exercise protocols, specifically, how intense they are. (The legend of the figure describing the exercise protocols contains a translation of the intensity scale used in these papers to the heart rate zones I use on this blog.) During the five years I have been writing this blog, I have found the translation of light, moderate, and vigorous exercise intensity recommendations of the medical community to something I can use problematic. That said, I have developed a consensus translation: Light = Heart Rate Zone 1, Moderate = Zone 2, and Vigorous = Zone 4. By that standard, almost all the recommended exercise in these papers would be classified as vigorous. At 5 to 6 hours a week of exercise, this would be more than twice the maximum amount of exercise recommended generally by the medical community. At that level of exercise, I am astonished at the 88% compliance reported.

Bottom Line

The report on Howden et al. in BBC News is overly sensational and in fact adds almost nothing to our understanding of the value of exercise at different ages. Some of this is because the article fails to explain the narrowness of the conclusions of the underlying scientific paper, that it applies to only one kind of heart failure, not overall longevity, and some of this is because of limitations of the paper itself weaken even this very narrow argument. There is extensive evidence in the literature in support of the value of exercise at all ages for increasing longevity, and in fact, when properly interpreted, even the claimed negative result pointed to in the BBC News article supports this conclusion. Thus, even at my ripe old age of 68, I should definitely keep riding.

    1) Howden et al: "Reversing the Cardiac Effects of Sedentary Aging in Middle Age—A Randomized Controlled Trial.
    Implications For Heart Failure Prevention." by Erin J. Howden, Satyam Sarma, Justin S. Lawley, Mildred Opondo, William Cornwell, Douglas Stoller, MD, Marcus A. Urey, Beverley Adams-Huet, and Benjamin D. Levine. Published in Circulation volume 137 [Epub ahead of print]. Year: 2018.
    2) Fujimoto et al: "Cardiovascular Effects of 1 Year of Progressive and Vigorous Exercise Training in Previously Sedentary Individuals Older Than 65 Years of Age" by Naoki Fujimoto, Anand Prasad, Jeffrey L. Hastings, Armin Arbab-Zadeh, Paul S. Bhella, Shigeki Shibata, Dean Palmer, and Benjamin D. Levine. Published in Circulation volume 122 page 1797. Year: 2010.

    Monday, March 12, 2018

    70 and Done?

    Log of my last seven months of cycling. I will comment on this record over the course of this post.

    I confess I have a Facebook addiction. The silver lining is that my compulsive reading of Facebook helps me keep up with some of my friends. My high school friend Paul (previously referred to as Peter* on this blog) doesn't have a Facebook account, but his wife Susan does. Thus, it was on Facebook that I found out about Paul's bicycle accident. I also read Susan's comment: "I told Paul his road riding days are over. He agrees." Of course I telephoned Paul to offer him my condolences, and he told me that this was not such a big deal, since he had already had planned to retire from cycling at age 70. Since Paul and I are roughly the same age, this is less than two years away for both of us. Is that a thing, off the bike at 70?

    Like Paul, I am also at a moment of truth, albeit a less acute one, and one based on physical fitness rather than safety. (I will return to the issue of safety at the end of the post.) As a result, I took Paul's remarks more seriously than I might have otherwise. My "moment" of truth (a moment that has lasted weeks) can be seen in the chart at the top of this post just by looking at the color of the "min/wk" column near the center of the chart. This color is based on the medical community's exercise recommendations. Weeks where I met the optimum recommendation of 300 minutes per week are are flagged in this column with a yellow background, those where I met the minimal recommendation of 150 minutes a week in green, and those where I didn't meet that minimum in white. My previous cycling routine had been devastated first by my wife's end of life care, then by her death, finally by the need to sell my house in Houston and move to California, with Hurricane Harvey making that difficult experience even worse. It was not until the week of 10/9/2017 that I was sufficiently moved into my new house in California that I could restart a cycling routine. For the next nine weeks, I managed to not only meet the optimal medical recommendation, but go well beyond them to a level of fitness that I hoped would easily prepare me for the Eroica California this spring and perhaps even riding with a local randonneuring club. And then, beginning the week of 12/11/2017, everything fell apart. What happened? In homage to the childrens' book series, I will describe it was A Series of Unfortunate Events.

    The first series of events, not unfortunate overall but which had an unfortunate effect on my cycling, was an uptick in my social life, a combination of out of town trips and visitors. During the nine weeks I was riding regularly, I found that cycling plus routine chores (cooking, grocery shopping, laundry, house cleaning) consumed 100% of my energy and time, leaving no time to take care of anything else. Thus, when I had to prepare for two weeks of somewhat challenging travel, the only way I could do that was to abandon my cycling.  During the following weeks, much welcomed house guests, babysitting, and dealing with my wife's estate kept me from reestablishing my routine. After four weeks of that, a truly unfortunate event occurred. My granddaughter developed a respiratory syncytial virus infection, and as sometimes happens, it was severe enough to send her to the hospital for a week. During that week, between running errands for her parents and visiting her in the hospital, I had little time and no energy left for cycling. And then, of course, I caught her virus and I was sick as a dog. As I write this six weeks later, I am still coughing.

    When I first became ill, my symptoms were severe; I had a fever, muscle ache, and did nothing but rest in bed. After a few days, I got over the worst of my symptoms and felt like I had nothing worse than a bad cold. In response, I started riding again, albeit extremely easy 30 minute rides around my neighborhood. Despite being so easy, they turned out to be too much; the day after even those easy rides I found my symptoms reproducibly got worse. So, I stopped trying to ride altogether, and it was only two weeks later that I resumed easy rides. They seemed to go well, so I resumed my "medium" (Pace) rides, my standard 2 hour/23 mile ride. My son had been urging me to try yoga for some time, so I did yoga on one of my off days as well. This was a disaster! My illness got much worse, and I have completely stopped riding again until I am symptom free. This means I will have lost a great deal of fitness, and worse, gotten out of the routine that I had worked so hard to build, but I don't see that I have a choice.

    So what about Eroica California and randonneuring? Eroica California is another unfortunate event. As it happens, I had drastically underestimated the difficulty of this ride, even in its shortest, 40 mile incarnation. What alerted me to my error was some posts on a bulletin board I follow, the Classic and Vintage (C&V) group of the Bike Forums site. Eroica California, which is modelled after the original Eroica held in Italy, is a ride to celebrate "classic" bikes, which is defined as bicycles built before 1988 which lack indexed shifters, clipless pedals, and other modern abominations. What I hadn't realized is that Eroica also features extremely difficult rides with unusually steep climbs on dirt roads; Eroica is derived from the same root as the word heroic. This Bike Forms member was posting to C&V to ask about options for putting sufficiently low gears on a classic bike to be able to make it up those climbs. "How bad can they be?" I asked myself as read his post, so I went to the Eroica California website and got my answer: up to 12% grades on rutted, muddy roads - and that's on the shortest, easiest ride! This is almost certainly more than I can manage on any bicycle (mountain bike included), and is out of the question on my 1960 Bianchi Specialissima with its very limited low gear options. So a few weeks ago, I notified my fellow Modesto Roadmen that I would not be joining them on this ride.

    How about randonneuring? I think I understood randonneuring better than I did Eroica, and so to the extent randonneuring was an option in 2017, it remains one in 2018, which begs the question of how realistic an aspiration it was in 2017. I may be learning that there are limitations imposed by my age which might not present themselves immediately or in the most obvious ways. I love bicycling, but it does makes me tired. Some of that tiredness is immediate; once I do a bike ride, I find it difficult to do anything else for the rest of that day. Some of that tiredness reveals itself only over time. If I push my bike rides day after day, I am more likely to pick up a virus that can knock me out of cycling for weeks. It can also leave me so tired that I can't get anything else done even on those days I don't ride. So, we'll see. I am going to concentrate on finding a sustainable ride schedule that optimizes my ability to deal with my long, long ToDo list, and take it from there.

    In summary, I am not setting my 70th birthday as any kind of deadline. I plan to ride as much as I can both before and after that date. I expect the amount of riding I will be able to do each year will be less than the year before, but I make no hard rule about that either; what I find I can do, I will do. There is one other concern; my friend Paul is not giving up cycling because he can no longer manage it physically, but because he no longer feels safe on the road, and safety is a separate, very important consideration. I already feel less safe on the road than I did in my prime, and in response, I am much more careful. Thus, I need to be willing  to face reality when the decline of my faculties make it unsafe to continue road cycling. To know when that is, I will both have to watch myself as well as solicit the advice of friends and family to tell me if they think the time has come. So, should I not die of something else before then, the day will come when it is time for me to hang up the bike. But rather than try to guess in advance when that will be, I will wait for the signs that tell me when I have gotten there, whether I it be at age 69 or 99.

    * Originally, I used pseudonyms to refer to my friends on this blog, but as I had a chance to talk to them, I decided this was unnecessary and have switched to referring to them by their real names.