Hypertrophy and the supply of blood to heart muscle

There are two main reasons why a runner might be concerned about the best way to train the heart. First, to improve running performance and second, to increases life expectancy or at least minimize the risk, albeit small, of heart attack during or after a race. As discussed in recent postings there are at least four aspects of heart structure and function that respond to training: blood supply, muscle hypertrophy, efficient fuel metabolism and heart rate variability (HRV). The relevance of HRV to perhaps less easy to appreciate, but as discussed in my post two days ago, decreased HRV appears to be a risk factor for sudden cardiac death.

In today’s post I want to examine cardiac muscle hypertrophy and improved blood supply. The reason for considering these two types of adaptation together is that the most important feature that distinguishes the healthy cardiac hypertrophy for the unhealthy hypertrophy that can occur in patients with cardiovascular disease, is the concurrent development of both muscle hypertrophy and blood vessels in healthy ‘athletes heart’, in contrast to hypertrophy without increased blood supply in pathological conditions. There is strong evidence for mutual interaction between the processes that promote normal development of muscle and blood vessels in the heart.

Back to the mini-pigs

Before examining the evidence from studies of human athletes, it is worth returning to the study of Yucatan mini-pigs which I mentioned a week ago. Pig heart has many similarities to human heart, but it is possible to do much more comprehensive investigations of changes in the pig heart. In that study by White and colleagues (J Appl Physiol 85:1160-1168, 1998) the pigs underwent an aerobic training program similar in volume and intensity to that typical of a long distance runner’s base-building program. The pigs were trained to run on a treadmill at a heart rate in the range 70-80% of maximum. In the first week they ran for 30 min on 5 days per week. The daily duration was increased by 5 min per day each week in the first 8 weeks and thereafter they continued to run for 70 min per day 5 days a week until 16 weeks.

During the first three weeks, the density of capillaries supplying blood to heart muscle increased, and then in the remaining weeks these capillaries apparently enlarged to become arterioles, so that by the end of 16 weeks, the cross sectional area of blood vessels had increased by 37%, and coronary blood flow had increased by 22%.

Capillary transfer reserve, which was assessed by measuring the increase in transport of diffusible molecules from blood to muscle when vessels were maximally dilated by administering a vasodilating drug, increased steadily throughout the study and at 16 weeks was 59% greater than at baseline. This demonstrates not that not only was the resting blood flow increased be training, but the capacity to increase the delivery of oxygen and nutrients to the heart under conditions of high demand was increased even more dramatically.

Left ventricular mass (relative to total body mass) had increased by 16% at 8 weeks and 24% at 16 weeks. VO2max increased by almost 40% in the first 8 weeks and thereafter only increased slightly. Thus a 16 week program of aerobic training produced an initial rapid development of new capillaries. Very little new sprouting of capillaries occurred after 3 weeks, but the total cross sectional area of blood vessels continued to increase, apparently reflecting the conversion of capillaries to arterioles, while muscle hypertrophy continued throughout.

Studies of humans

Many studies have revealed that athletes exhibit cardiac hypertrophy relative to sedentary controls, but there are remarkable few longitudinal studies that allow an estimate the magnitude of the effect of a particular training program on cardiac structure and function. Furthermore, it is necessary to consider the issue of the stage in an athletes career. One might expect the greatest gains in the early years, though of course this must be set against the expectation that training volume and intensity should be less in the early stages of a running career.

Moderate intensity training in novices

In a study by Rodriguez et al Am J Cardiol.;97:1089-92, 2006), 23 sedentary men in their late 20’s and early 30’s undertook a 6 month program of moderate-intensity aerobic training (1 hour/day, 3 times/week). This program achieved a 14.5% increase VO2 max; a 4 beat per minute decrease in average resting HR; a 15% increase in left ventricular mass index; and approximately a 6% increase in thickness of both the septum separating the ventricles and the posterior ventricular wall (assessed by Doppler echocardiography). Somewhat surprisingly there was not a statistically significant increase in stroke volume. Nonetheless, this study clearly demonstrates substantial left ventricular hypertrophy and also an associated increase in VO2 max during the type of 6 month aerobic program that might be recommended for novice who has recently taken up running.

Intense training in elite athletes

Perhaps of more relevance to committed athletes is a study of changes during the 6 months training commencing at the end of a 6 week off-season, in a cohort of 22 young elite athletes, by Naylor and colleagues from University of Western Australia (J Physiol 563; 957-963, 2005). The athletes (all rowers) had a mean age of 20, suggesting a prior career of 3-5 years duration. At the beginning of training after the off-season they had a mean left ventricular mass of 235 gm compared with 178 gm in a group of matched recreationally active control subjects. After three months training (twice daily, 6 or 7 days per week), the athletes had increased their left ventricular mass even further to 253 gm and it then remained stable around this level (with a value of 249 gm at 6 months). Thus it appears that there is a cumulative increase in hypertrophy over years of training, at least in young athletes, and training in the new season can produce a further increase around 7% in the first 3 months followed by a plateau period extending out to 6 months (ie a lesser relative increase than the 15% reported by Rodriguez in the 6 month program in novice subjects).

However the even more interesting measurement in the elite athletes studied by Naylor was left ventricular flow propagation velocity, an indicator of speed of left ventricular filling. At the beginning of the season, this quantity was less in the athletes than in the control subjects. Rapid filling is required to make the most of the benefits of greater contractility. It appears that a hypertrophic heart is of little value if it is not regularly exercised. However left ventricular filling rate improved throughout the 6 months of training, to a level marginally higher than that in the non-athlete control subjects. Thus by the end of the 6 month training period the athletes had hearts that were not only larger than the controls but also filled at least as rapidly.

It should be noted that the rowers studied by Naylor engaged in a mixed training program including both aerobic and resistance training. It was once believed that aerobic training produced predominantly an enlargement of the ventricular diameter, and hence stroke volume (so called eccentric hypertrophy), while resistance training produced thickening of the ventricular walls (concentric hypertrophy). More recent evidence indicates that enlarged diameter does predominate slightly in endurance-trained athletes whereas increased wall thickness predominates slightly in resistance- and static-trained athletes, but the differences are not dramatic (Barbier et al, Herz 31, 531-543, 2006).

Mechanical mechanism of hypertrophy

The mechanism of hypertrophy can be investigated at various levels. At the level of large scale mechanical processes it is well understood that increased filling of the chambers of the heart will stretch the vessel walls and this will lead to increased tension in the muscular walls which will in turn result a more powerful contraction (the Frank Starling Principle) – similar to the greater power of skeletal muscles during plyometric exercise. This greater stretching acts as a stimulus to hypertrophy.

Underlying molecular mechanisms

However perhaps more interesting is the mechanism at the level of the molecular processes that go on within the muscle cells. As is the case in many biological processes, effects occurring at the cell surface (eg mechanical effects such as stretching or the binding of messenger molecules) initiate a complex cascade of signaling within the cells. This intracellular signaling usually involves activation of enzymes that add phosphate groups to other proteins thereby changing their shape and function, and these proteins then act on others creating a cascade of effects. The signaling processes lead to the expression of genes (that is, the translation of the DNA code) to produce new proteins, which might themselves be either additional signaling molecules, or the proteins that carry out the primary function of the cell – e.g. contractile proteins.  Thus the  end result of the cascade of signals is the production of proteins that carry out the main functions of the cell. 

One of the pathways involved in cardiac muscle hypertrophy is the Akt pathway (Shiojima & Walsh, Genes Dev. 20: 3347-3365, 2006). Akt is activated by various extra-cellular stimuli. One of the mechanisms of activation is via insulin-like growth factor (IGF). A comparison of professional soccer players (who trained for 10 hours per week) with non-athletes, revealed that IGF formation is associated with cardiac hypertrophy (Neri Serneri et al, Circ. Res. 89;977-982, 2001). The authors concluded that increased cardiac IGF is likely to be a major contributor to cardiac hypertrophy in athletes. Akt is a signaling molecule that itself acts on three different pathways: pathways involving GSK-3, m-TOR, and FOXO. [The names of signaling molecules should be read in the same spirit as Jabberwocky, or perhaps, like the names of fundamental particles in physics – some names have an understandable serious origin but others sound like a private joke between the scientists who created them]. GSK-3 regulates cardiac muscle hypertrophy; m-TOR regulates growth of small blood vessels (possibly be the well known vascular endothelial growth factor, VEGF). Akt switches off FOXO, which plays a role in protein degradation.

A crucial feature is that transient bursts of Akt signaling promote concurrent development of both muscle fibres (hypertrophy) and also development of capillaries. Concurrent hypertrophy and increase in capillaries is the characteristic of healthy hypertrophy. However paradoxically sustained Akt activity can result in the hypertrophy without accompanying development of small blood vessels. This is the characteristic feature of pathological hypertrophy seen in several form of heart disease. Although I am not aware of any evidence that excessive training can lead to hypertrophy without increased blood supply to the heart muscle, the observation that sustained Akt activation can have potentially pathological effects points to the need for the body to have mechanisms that protect against excessive training. My own speculative hypothesis is that the over-training syndrome, which acts to discourage an athlete from continuing with an excessive training routine, might indeed be a defensive mechanism invoked by the body to protect us from ourselves. I will return to this theme in a later post.

Practical conclusions

So in conclusion, the main goals of a distance runner, namely improving blood supply to heart muscle and producing the hypertrophy associated with an increase in stroke volume, can be met simply an aerobic program along the lines undertaken by the Yucatan mini-pigs studied by White and Bloor. However, the study by Naylor of elite athletes in the six months following the off-season demonstrates the complexity of the relationship between prior training history and the improvement in cardiac function. In particular, the evidence indicates that despite the persistence of previously acquired hypertrophy, deterioration in ventricular filling speed during a 6 week off-season might offset any advantages of the pre-existing hypertrophy until many months after the resumption of vigorous training. There is not a great deal of evidence to demonstrate superiority of one training regimen over another for improving cardiac function, but nonetheless, I will review what evidence there is, in the near future.

2 Responses to “Hypertrophy and the supply of blood to heart muscle”

  1. Ewen Says:

    Canute, did you find anything about training methods to improve stroke volume (apart from general aerobic training). I do remember reading something about interval training where the HR is repeatedly accelerated from rest to around 90-95% as being an efficient way to do this.

    The 6-week off season was illuminating – shows that it’s probably best not to have too long an off season – esp as some runners have an off season after both summer and winter.

  2. canute1 Says:

    Ewen, There is no compelling evidence regarding the best training method for increasing stroke volume, but a combination of empirical evidence with information about mechanisms does provide some pointers, which I will discuss in my next blog.

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