Heart rate variability

Heart rate variability, as the name implies, is variability in the duration between consecutive beats.  In the ECG, it is variability in the time interval between consecutive R waves in the QRS complex that represents the electrical events of ventricular contraction.  In general, the heart beats faster during inspiration and more slowly during expiration.  These variations are governed by the autonomic nervous system, which is responsible for the regulation of many of the body’s internal organs and in particular, coordinates the fight-or-flight reactions that prepare our body to deal with challenging situations.  There are two distinct divisions of the autonomic systems: the sympathetic system which tends to accelerate the heart and the parasympathetic system which produces deceleration. 

Almost certainly HRV is a crucial importance to the athlete, though the details are still a subject of debate.  There are three main issues:   1) loss of HRV  is potentially a useful indicator of the stress associated with training, and there is evidence suggesting that adjusting training schedules according to changes on HRV can increase the quality of the training and diminish the risk of over-training; 2) loss of HRV is a fairly reliable indicator of sudden cardiac death in individuals with heart disease and some evidence indicates that it has similar implications even when there is no other evidence of heart disease; 3) a resilient heart with high HRV might in fact function more efficiently and hence improved HRV might itself contribute to improved performance.   In the next few posts I will attempt to examine all three of these issues, and also to address the question of how HRV might best be increased by training.

Before examining the evidence that training might have either beneficial or deleterious effects on HRV, I decided  to look at HRV in my own heart.  Both Polar and Suunto manufacture hear rate monitoring equipment that provides an estimate of HRV, but I am still undecided about the value of investing in such equipment.   Furthermore, I thought it would be interesting to examine not only heart rate variability, but also the shape of the various peaks and troughs that make up the ECG.  I rigged up a system with a lead attached to each forearm, and fed the signal to some electrically isolated amplifiers, before digitizing it so that I could subject it to some detailed analyses. (Isolation of the amplifiers is crucial for safety).  The trace recorded with this ad hoc system in not a clinical ECG, but nonetheless corresponds quite closely to lead 1 in a clinical 12 lead ECG.  Lead 1 represents the difference in voltage between left and right arms.

 

My  ECG

The ECG reflects the flow of the electrical currents that produces contraction of the heart muscle.  The current flow produces currents in the surrounding body tissues and provides a signal detectable on the body surface.  The magnitude and average direction of the current flow determines the size and shape of the various peaks in the ECG.  For our present purposes, the feature of greatest important is the rhythm, and in particular, the variability of the interval between beats.  However, a substantial number of athletes have minor abnormalities of the shape of the waveform.  Follow-up studies indicate that these abnormities are generally benign and do not create a high risk of heart attack, though the issue of distinguishing clearly between normal variation seen in athletes and pathological variation is still a somewhat vexed question.  Therefore, I was interested to examine the waveform to see whether or not I have significant abnormalities.  I am an amateur in the interpretation of ECG’s, so if a cardiologist happens to read this, I would be delighted to hear whether or not I have interpreted things correctly. 

ECG and inter-beat interval

The figure on the left shows the ECG during two successive heart beats, while the figure on the right shows the variation in inter-beat interval over a period of about 80 seconds.  The waveform looks fairly normal to me (as an amateur). 

Atrial contraction

The P wave reflects spread of the electrical signal from its generation at the sinoatrial node, though the walls of the right and left atria, and in my recording is about 80 milliseconds wide and has a height of 0.08 mV.  After an interval of around 195 millisec, the P wave is followed by a QRS complex.  The PR interval is the time between sino-atrial node firing and the firing of the AV-node which initiates ventricular contraction.  It is an important indicator of transmission of the electrical signal from atria to ventricles. The normal value is around 200ms.  Very short values might indicate a potentially serious conduction abnormality known as the Wolfe-Parkinson-White syndrome, while long values might indicate blockage of transmission, so it is reassuring that the duration of my PR interval seem fairly normal.   Between P wave and QRS complex the trace should be fairly flat, though in my case there is a slight downwards slope.  I do not know if this has any significance. 

Ventricular contraction

The QRS complex reflects the spread of the electrical signal that causes depolarization of the muscle in the walls of the ventricles.  The depolarization of the muscle cell membrane produces the muscular contraction that ejects the blood from the ventricles.  The negative Q wave represents the spread of electrical signal downwards and left-wards to the apex of the heart and the large Q wave reflects the spread around the lateral walls upwards and predominantly rightwards from the apex. In some leads of the ECG, R is followed by a small negative deflection known as the S wave, though due to the direction of current flow at this time, the S wave often small in lead 1, and in my ECG, it is scarcely discernible at all.    In a healthy heart the width of the QRS complex should be less than 120 ms.  In my case it is only about 60 ms.

Ventricular repolarization

The final peak of interest is the T wave, a hump occurring about 350 ms after the end of the QRS complex in my trace.  This denotes re-polarization of the heart muscle, making it ready to contract again.  Prolongation of the QT interval occurs in a number of pathological conditions and can also be an unintended side effect of various medications. Because it tends to be shorter at high heart rates, it is usual to estimate a corrected value known as QTc which allows for variation in the heart rate.  In my recording QTc is about 300 ms.  The usual value is around 420 ms, so I do not have any evidence of a pathologically long QTc.

One feature that is of great clinical importance is the ST segment.  This is depressed when the heart muscle is deprived of oxygen and can be elevated once the heart muscle has been damaged.  The ST segment should be flat, but in my case it rises steadily for about 100 ms preceding T wave.  As far as I am aware, this upward slope of the ST segment is quite common in athletes, and possibly denotes thickening of the ventricle walls.  The point at which ST elevation of depression is usually measured is 60 millisec after the end of the QRS complex.  At this point, my trace shows no evidence of either depression of elevation, so I am inclined to interpret this picture as indicating a healthy though perhaps slightly hypertrophic heart.

HRV

Now to the important issue for our present discussion.  My average heart rate during this recording was 46 beats per minute, which I think  is fairly typical of a fit athlete when sitting down, trying the relax but nonetheless, with my mind focused on making sure the equipment is continuing to function.  However even more striking is the variation of the heart rate.  As can be seen from the right hand figure, over the course of about 80 seconds the inter-beat interval varied from 1.1 sec (HR 54 bpm) to 1.5 sec (HR 40 bpm).  The normal variability in beat-to-beat interval is less than 10%.  So I definitely have substantially increased heart rate variability.

Even  more interesting is the time-scale of the variation. It can be seen from the right hand figure, that the dominant fluctuation are rapid (ie high frequency) fluctuation occurring on a time is around 2-4 beats (i.e over a period of 4 seconds corresponding to a frequency of  0.25 cycles/sec.)  These high frequency fluctuations are characteristic of the parasympathetic nervous system, which in general is associated with relaxation and recovery. 

However, closer inspection also reveals underlying variation on a time scale of around 30-40 beats (40-50 seconds) corresponding to a frequency of 0.02 cycles per second.  Slow fluctuations on this time scale are characteristic the action of the sympathetic nervous system – the part of the autonomic nervous system that promotes fight or flight.  So I am encouraged to observe evidence of a balance between parasympathetic and sympathetic activity, but with a particularly strong parasympathetic component.

 

Sympathetic-parasympathetic balance: the Poincare plot

There is an intriguing though somewhat complex way of quantifying the relative contributions of parasympathetic and sympathetic nervous system to hear rate variability, known as the Poincare plot.  The Poincare plot is a scatter plot in which each heart beat is represented by a point in a two dimensional plane, with the value of the  inter-beat interval preceding that beat is plotted on the horizontal axis and the value of the following  inter-beat interval on the vertical axis.   This scatter plot is shown on the figure below, for the same data as is shown in the figure above.  The points look a bit like a swarm of bees scattered around a line that runs diagonally upwards at 45 degrees. 

Sympathetic - parasympathetic balance: the Poincare plot

 

The interpretation requires some concentrated thinking but is worth the effort.  Imagine that the heart rate variability is produced entirely by sympathetic nervous system activity.  Such fluctuations occur on a slow time scale – typically varying substantially over a period  40 beats or more. Therefore for consecutive beats, the inter-beat interval is almost unchanged.  The points representing those near identically spaced consecutive heart beats must lie near the 45 degree line.  However, if there is a slow drift in values of inter-beat interval over time, due to fluctuation in the input from the sympathetic nervous system, then the points will wander up and down the 45 degree line.

On the other hand, if the fluctuations are driven by the parasympathetic nervous system, they occur on a time scale of a few beats, and the beat by beat variation will be large.  Therefore many heart beats will be represented by points that lie far away from the 45 degree line

If we draw an ellipse that is just large enough to include most of the heart beats (allowing that there will usually be few outliers that buck the general trend) then this ellipse will have one  axis pointing along the 45 degree line and the other axis at right angles to this.  The length of the axis along the 45 degree line represents the amount of sympathetic drive and the length axis at right angles to this represents parasympathetic drive. 

In individuals a high risk of heart attack the ellipse is a long thin cigar shape lying along the 45 degree line.  For individuals with a good balance between parasympathetic and sympathetic input, the ellipse is almost round. I was delighted to find that for me, the ellipse is fat and almost round.

 

Summary

So in summary, I am quite pleased with what my little experiment showed.  As far as I can tell, the shape of my ECG trace is near normal, apart from the upward slope of the ST segment that I understand is relatively common in athletes.  My heart rate is slow, but even more importantly, there is a large variability, driven by a good balance between parasympathetic and sympathetic activity.  I am re-assured that I appear to be at low risk of a heart attack.

 

I suspect that the substantial HRV is the product of my training.  In future posts I will examine the evidence regarding the types of training that are most likely to improve HRV and also explore the question of whether measurement of HRV does in fact provide not only an estimate of likely risk of a heart attack, but also might be a useful indicator of the over-training syndrome, and hence provide a useful way to adjust one’s training schedule.

High intensity v low intensity training for the heart

My post on 20^th June looked at the evidence  that training can produce both cardiac hypertrophy and increased blood supply to the heart muscle – the combination  of features that distinguish healthy hypertrophy for the unhealthy hypertrophy seen in some cases of cardiovascular disease.  The evidence from studies of pigs on treadmills and novice runners following a moderately demanding aerobic program is that several months of aerobic training can produce a substantial increase in the mass of the left ventricle – eg a 15% increase in mass after 6 months training in Rodriguez’s study of healthy but previously untrained young men (Am J Cardiol. 97:1089-92, 2006). This increase was associated with increased ventricular diameter and increased thickness of the muscular walls of the heart.  There was an associated increase in VO2max, a direct measure of aerobic capacity and a strong predictor of performance over middle and long distances.

Naylor’s study of elite athletes also demonstrated an increased ventricular mass after 6 months training in elite athletes (J Physiol 563; 957-963, 2005), but the increase was less than in the novices studied by Rodriguez and there was a disconcerting observation that despite pre-existing hypertrophy from previous years of training, at the beginning of the study (after a 6 week lay-off) the elite athletes had evidence of slower filling of their ventricles, which would reduce the capacity to utilize the additional muscle mass effectively.

 The contrast between the studies by Rodriguez and Naylor demonstrates that the benefits of a training program vary depending on the prior training status of the athletes.  Consequently, it is difficult to provide a clear answer to a very simple question: what form of training is likely to be most beneficial for improving cardiac function.

 The alternative to examining the results of studies of training programs is to examine what we know about the mechanism of hypertrophy.  Unfortunately, rapidly growing knowledge about the mechanisms by which the body responds to training has revealed just how complex these mechanisms are.  On account of the scope for unpredictable interactions between many variables, prediction of the final outcome on the basis of simple theory is unreliable.   My own view is that the most sensible approach is to combine what we know about mechanisms with the evidence from studies of training, and test that against one’s own experience – since  no two individuals are identical in genes and experience and therefore each person has to find out what works for him or her.

 

Speculation based on theory

First we need to ask what variable is of greatest interest.  For the middle and long distance runner, the most important demand on the heart is to deliver a large volume of blood bearing oxygen – the capacity to do this is known as cardiac output – the volume of blood delivered per minute.  This is the product of heart rate and stroke volume.  From the point of view of aerobic performance, the ultimate measure  is VO2 max, the maximum rate of utilization of oxygen. This is calculated by multiplying  cardiac output by oxygen extraction fraction.  Oxygen extraction fraction is a property of the skeletal muscles determined by capillary density and density of mitochondria in the skeletal muscle.  But for the present purpose we are concerned about training the heart.  Therefore, the trainable quantity if greatest interest for our present discussion is stroke volume.

The acute effect of ventricular filling

 Stroke volume is determined largely by the diameter of the ventricles but also by the efficiency of filling of the ventricles and the power to eject blood from the ventricles.  One of the important features of the function of cardiac muscle is the fact that stretching immediately prior to contraction produces a more powerful contraction – this is the Frank-Starling principle. As heart rate and cardiac output rise in response to demand for oxygen in the muscles, the return of blood from the periphery rises, greater stretching occurs during filling, and a more powerful contraction is produced.  In a trained athlete, stroke volume normally increases as the  cardiac output, and therefore the amount of blood returned to the heart, increases, reaching its maximum when heart rate reaches its maximum. 

In the early phases of training, increase in blood volume leads to greater filling and more powerful contraction.  Incidentally, either dehydration or the forcing of fluid into body tissues that accompanies an increase in blood pressure, decreases the volume of blood returned to the heart, so stroke volume falls and heart rate needs to rise higher to compensate to maintain a given cardiac outpt. VO2 max will be truncated because maximum heart rate does not change substantially. 

 The long term effects of ventricular filling

 Not only does increased cardiac filling promote an immediate rise in force of contraction, but the stretching of the heart muscle at the end of the filling phase (diastole) acts as a trigger to hypertrophy, apparently via the Akt signaling within the heart muscle cell, which ultimately leads to both the generation of additional contractile proteins and also the parallel development of capillaries, as discussed in my blog a few days ago.  This hypertophy will lead to an increase in both the diameter  of the ventricles and also the thickness of the walls of the ventricles, as demonstrated in the study by Rodrigues et al (Am J Cardiol. 97:1089-92, 2006).

So the most efficient form of training for increasing stroke volume and for the associated development of capillaries supplying the heart muscle is likely to be fairly vigorous exercise that produces a large amount of filling of the ventricles during diastole.  It would be expected that the  greatest benefit per unit of time spent training will be gained by training near VO2 max – though of course the overall picture must take into account the risks  associated with training at this level.  We will return to that issue again in the future.

The myoglobin effect

However one additional point needs to be made. If training is to be above the lactate threshold, then each effortful interval must be relatively brief – but not too brief, because of the phenomenon of buffering by myoglobin. At the beginning of an effortful interval, oxygen attached to myoglobin in the muscles can meet the metabolic needs for a period of a minute or so, so the demand for cardiac output does not reach a peak until about two minutes after the start of the effort.  Therefore, one might expect that intervals of three or four minutes duration would proved the best value for time spent (though alternatively one might do shorter intervals if the rest period is very short (eg 10-20 sec) so that myoglobin is only partially  replenished during the rest period).

 Matching observation to theory

How does observation match theory?  There are very few studies that have directly compared the changes in stroke volume after a program of high intensity interval training compared with lower intensity aerobic training. The only one I know of is by Helgerud and colleagues from Trondheim in Norway (Med Sci Sports Exerc. 39(4):665-71; 2007). They randomly allocated 40 moderately trained male participants (with initial VO2 max around 60 ml/min/kg)  to one of four training groups for 3 sessions per week for 8 weeks:

 1) long slow distance (LSD) (70% maximal heart rate);

2) lactate threshold (85% HRmax);

 3) 15:15 interval running (15 s of running at 90-95% HRmax followed by 15 s of active resting at 70% HRmax); a session included 47 x15 s effort intervals.

4) 4 x 4 min of interval running (4 min of running at 90-95% HRmax followed by 3 min of active resting at 70%HRmax).  

The amount of work in each session was adjusted to that the total oxygen consumption was similar is all four groups. 

The two interval training programs resulted in a significantly greater improvement of VO2max (5.5% for 15:15 and 7.2% for 4 x 4 min intervals than the low intensity aerobic and lactate threshold sessions. Furthermore stroke volume increased by approximately 10%  after each of the high intensity interval programs.  Thus, it appears that compared with low intensity aerobic or lactate threshold training, high intensity interval training produces greater improvements in VO2 max  and parallel increases in stroke volume, in accord with expectation based on theoretical considerations.

 High intensity is best, but in moderation

Thus the most efficient from of training for producing an increase in stroke volume and VO2 max appears to be high intenirty interval training.   This certainly does not mean that a training program should consist entirely of high intensity sessions for two reasons.  First, it is necessary to take account of the need to train the leg muslces as well. Increasing capillaries and mitochondria in leg muscles, and also developing the ability to withstand eccentric contractions of the leg muscles for the duration of the intended race are also important aspects of optimizing racing performance.  At least for long races (half-marathon and marathon) training the leg muscles to cope with multiply repeated eccentric contractions at each footfall is crucial, and this requires a substantial training volume.  The second issue is avoiding too much stress on the heart.  The crucial issue here is maintaining heart rate variability (HRV).  HRV can be improved by training, but both excessive volume and excessive intensity of training can impair HRV.  I will examine this issue in more detail in my next posting.

 Nonetheless the simple conclusion with regard to increasing cardiac output is that both medium intensity aerobic training (as employed in the study by Rodriguez, considered in my post on 20^th June) and high intensity interval training can produce benefits, but high intensity interval training is the more efficient.

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.

Heart rate variability: is the debate between Noakes and Ekblom about the wrong question?

In my recent post about training the heart I listed three aspects of heart structure and function that respond to training: blood supply; muscle hypertrophy; and fuel metabolism. There is a fourth which is less easy to understand, but might actually be the most important. So bear with me.  We will get back the the reality of every-day training before too long.

The fourth trainable aspect is heart rate variability (HRV); the variability in heart rate that occurs on a time scale of 2 to 20 seconds. It is well established that the heart rate varies breath by breath, inceasing during inspiration and decreasing during expiration, mainly due to input from the parasympathetic nervous system during expiration. Furthermore it is established that loss of this heart rate variability is a predictor of risk of sudden cardiac death. Finally, many stressors, including hard training or racing cause a reduction in heart rate variability and the degree of this reduction is correlated with the length of time it takes for the body to recover.  It should be noted that many different types of stress, possibly involving signals from different systems within the body, can produce a reduction in HRV.  It appears that a healthy heart requires resilience

Back to the central governor

For the past decade Tim Noakes in Capetown (J Appl Physiol 106: 347, 2009 and 106:341, 2009.) and Bjorn Ekblom from the Karolinska Institute in Stockholm (J Appl Physiol 106:339-341, 2009) have debated the issue of the central governor – a proposed governor in the brain that acts to limit power output so as to protect the heart. The debate between Noakes and Ekblom centres on the fact that even at a power output around VO2 max, there is good evidence that under many circumstances there is substantial coronary reserve (ability to increase coronary blood flow) and also ability to increase cardiac work. Ekblom has invoked this evidence to oppose Noakes theory of the central governor [Ekblom, Scand J Med Sci Sports 2000: 10: 119–122; J Appl Physiol 2007; 102:781-786 ] As far as I can see, Ekblom has got the best of the argument, at least in the eyes of many professional physiologists, though many athletes are more sympathetic to Noakes.

In my view, both Ekblom and Noakes might be asking the wrong question. If indeed it is loss of heart rate variability rather than simple deprivation of oxygen that puts the heart at risk, an effective governor will be geared up to identify serious decrease in HRV and at that point, limit the body’s power output.

Why might HRV be the key?

This seems plausible for several reasons. First of all, most deaths during or after a marathon do not occur when the heart is likely to be acutely deprived of oxygen, but rather following cumulative stress (Journal of the American College of Cardiology, vol 28, pp 428-431, 1996).  Cumulative stress decreases HRV. Secondly, the fact that decrease of HRV predicts recovery time from a race or training suggests that the brain not only keeps track of HRV but sets this in the context of how much longer the race will be. This would explain the observation that it is possible to sprint at the end of a marathon even when it was impossible even to increase pace slightly after hitting the wall a few miles earlier.

Why is it hard to improve max HR by training ?

This proposal provides a simple answer to the question of why peak heart rate is virtually non-responsive to training and tends to decrease with age, thereby resulting in decreasing VO2max and decreasing aerobic performance. A rise in HR is associated with an increase in sympathetic input; a decrease in parasympathetic input; and a decrease in HRV. At a certain heart rate, it would be dangerous to decrease parasympathetic input any further. As the tissues of the heart become stiffer with age, this might be expected to occur at a lower HR. This raises the crucial issue of whether training can prevent this deterioration. I will return to that issue later.

Nerves supplying the heart

To propose that Noakes and Ekblom have been arguing about an irrelevant measurement is a rather a bold claim to make, so you might reasonably expect me to provide some better evidence. The first body of evidence concerns the nerve supply to the heart. There is an internal nerve supply in the heart (Arora et al , Am J Physiol Regul Integr Comp Physiol 285: R1212–R1223, 2003), and also an external input from the two main divisions of the autonomic nervous systems: the sympathetic system which makes the heart beat faster and the parasympathetic system that slows the heart down

Sympathetic input rises under stressful circumstances while parasympathetic input increases during relaxation or recovery. Sympathetic input to the heart causes slow oscillations in heart rate (on a time scale of 7-20 second2); parasympathetic input causes more rapid oscillations on a time scale of 2-7 seconds. There is a great deal of evidence that a preponderance of slower parasympathetic oscillations predicts a longer life. Spinal cord stimulation which is likely to send parasympathetic signals to the heart tends to overcome the dangerous effects of oxygen deprivation in a diseased heart, and can be an effective treatment for angina (Foreman et al Cardiovascular Research 47;367–3750: 2000).

The heart talks to the brain

Furthermore the passage of nerve messages between heart and brain is not one way. The nerves in the heart send messages back to the brain, providing a means of informing the brain about the current variability and stress level. However the internal cardiac nerves cannot by themselves produce the heart rate variability that appears to be a feature of health. In a dog with the sympathetic and parasympathetic input removed surgically, coordinated rapid contraction of the heart occurs but HRV is abolished (Murphy et al Am J Physiol Regulatory Integrative Comp Physiol 266:1127-1135, 1994). There is a large body of evidence indicating that HRV predicts the amount of extra oxygen that will be required after a hard training run – and this does not appear to be simply a matter of the brain estimating the accumulation of lactate, at least when the heart has been under substantial stress (Dixon, Cardiovasc Res. 26(7):713-9,2000).  Suunto, who manufacture a heart rate monitor that can measure HRV, claim that loss of HRV might be a useful indicator of over-training. I think the evidence regarding detection of over-training is complex, but there appears to be a degree of truth in Suunto’s claim.

What does this mean for planning a training program?

If some or all of these speculations are correct, the crucial issue for the athlete is whether HRV can be improved by training. The good news is yes (eg Dixon, Cardiovasc Res. 26(7):713-9, 1992). In the near future I will return to the discussion of how we can best train the heart, and at that point I hope to provide a good answer to this question.

Meanwhile, with regard to Ewen’s comment after my post on Saturday suggesting that he is limited by his muscles, not his heart, I agree, but I would propose that it might be that his current strenuous training and relativley unremitting program might have led to a reduction in HRV. Hence, his central governor is acting to stop him pushing himself too near to VO2max. Ewen, do you have a HRM that will provide you with HRV values? I apologize in advance if I am shooting off with an unfounded hypothesis.

Cardiac fitness

Recently I said that I would post some thoughts on running and the heart. The topic is vast. Today I want to address the question of whether athletic performance is limited by fitness of the heart or fitness of the skeletal muscles. This has been a topic of debate since the 1920’s when Nobel prize winner, AV Hill, first put forward the concept that a governor protects the heart by ‘slowing the circulation’ (Quart J Med 1923;16:135–71). In the past decade, two of the main protagonists in the debate have been Tim Noakes in Capetown and Bjorn Ekblom at the Karolinska Institute in Stockholm. As might be expected, the answer appears to depend on circumstances.

Can cardiac work increase at power output above VO2max?

Ekblom and colleagues (J Appl Physiol 2007; 102:781-786) measured oxygen utilization (VO2), cardiac output, heart rate and blood pressure in 8 well trained young men during two brief bouts of exercise (lasting about 4 minutes each) at a power output above that achievable at VO2 max. During these bouts of ’supramaximal’ exercise (i.e. above power output at VO2 max), blood pressure rose with increasing power output despite constant VO2 and heart rate, demonstrating that the work done by the heart continued to increase. This suggests that the cardiac work under the circumstance of that study was not the limiting factor.

What happened to cardiac output when the oxygen supply is low?

In contrast, in a review of studies of cardiac output when running at high altitude (or other circumstances where a decreased amount of oxygen is delivered via the lungs) by Noakes’ team, suggests that under these circumstances, cardiac output falls as availability of oxygen falls (Journal of Experimental Biology 2001; 204, 3225–3234). If the heart was not the limiting factor, it might be expected that cardiac output would rise to maintain the rate of delivery of oxygen to skeletal muscles. However, this might be a risky strategy. Increasing cardiac output and therefore increasing the oxygen requirements of the heart, when the availability of oxygen is less would create the risk of starving the heart muscle of oxygen, thereby creating the risk of disturbance of the exquisitely synchronized rhythm of heart muscle contraction and potentially fatal fibrillation. Perhaps not surprisingly under conditions where oxygen delivery via the lungs is less (eg at high altitude), it appears that Noakes ‘central governor’ takes action to prevent the heart being damaged with catastrophic consequences.

My central governor

My asthma frequently restricts the supply of oxygen to my lungs. I do not regularly measure my peak expiratory flow before and after training, but when I do, it typically falls from around 500 litres per minutes to around 250 litres/minute during a training session. The most extreme I have observed was a fall from 610 litres per minute to 130 litres per minute. My subjective experience is that over shorter distances, I am limited mainly by my ability to get enough oxygen into my lungs. Interestingly, I find it very hard to get my heart rate much above 150 (though on some occasions I do manage to get it to 160). I suspect that my non-conscious brain is very reluctant to allow me to push myself to the limit. So the effect of diminished oxygen supply is not a compensatory increase in heart rate, but rather my brain appears to curtail how fast I can run, possibly to protect my heart.

In fact I have little desire to push myself to VO2 max and beyond at present. I would quite like to run a fairly fast mile again one day (ie, anything faster than 6 minutes – the pace that I once regarded as the slowest worthwhile training pace even for long distance runs, but at present I am unable to sustain that pace for even one mile), though I am prepared to put that day off until my asthma settles. I use a steroid inhaler which keeps my asthma under moderately good control. So far I have resisted taking oral steroids; I would only accept the risks of oral steroids if asthma was seriously interfering with my everyday life. For the time being I would prefer to work on gradually building my aerobic capacity and increasing the endurance of my leg muscles, since those are the characteristics that limit me when running long distances in the aerobic zone. Nonetheless, I am also eager to increase my cardiac fitness as much as possible to give myself a good buffer zone so that I can safely push myself a little beyond lactate threshold at the end of a race.

Creating a safety buffer zone

Cardiac deaths among athletes are not restricted to those competing in short anaerobic events. The risk of cardiac death in the 24 hours after a marathon is estimated to be around 1 in 50,000 (Journal of the American College of Cardiology, 1996; 28, 428-431). This is a small risk but nonetheless, even among those who do not suffer asthma or any known cardiac disease, it would seem to be worthwhile to increase cardiac fitness as much a possible before strenuous endurance events. But this raises the question of how can we best make the heart fitter?

First we must ask what aspects of heart structure or function can be strengthened by training. There is good evidence that training can produce improvements in three main domains:

1) Hypertrophy of cardiac muscle. Both ventricular diameter (and hence stroke volume) and also cardiac wall thickness can be increased by training. When I was young, there was much discussion as to whether or not the hypertrophy of an athlete’s heart was healthy. In non-athletes, a large heart can be a sign of serious disease. In the past few decades it has become clear that the hypertrophy seen in athletes is generally healthy. Unlike pathological hypertrophy, which is usually associated with decreased coronary reserve ( decreased ability to increase blood flow in the coronary arteries when required), in athletes cardiac hypertrophy is usually associated with increased coronary reserve (Hildick Smith and colleagues, Heart 2000;84:383–389).

2) Increased capacity of small blood vessels supplying the heart muscle.  The evidence for this was controversial for some years because some measurements suggested that capillary density was not increased in athletes compared with sedentary people. However, this debate was resolved by a study of Yucatan mini-pigs carried out by White, Bloor and colleagues (J Appl Physiol 85:1160-1168, 1998.) Pig heart resembles human heart in many ways. White and colleagues trained their pigs on a treadmill for 16 weeks, following a program that entailed a gradual increase from running for 30 minutes, five days per week at 70-80% maximum heart rate, up to running for 70 minutes, 5 days per week, after 8 weeks. The pigs maintained that training load for a further 8 weeks. After the initial 3 weeks capillary density had increased, but at 16 weeks capillary density was not greater than at baseline – however the number of arterioles (blood vessels intermediate in diameter between capillaries and arteries) was increased, indicating that number of capillaries had initially increased, but subsequently the diameter of these capillaries increased and they became arterioles.

The most important aspect of coronary blood supply for the athlete is how much it can increase above resting level when required. This is known as coronary reserve. It is probable that coronary reserve depends not only on the number and diameter of blood vessels, but also on the hormonal or other biochemical mechanisms that produce dilation the blood vessels when demand increases. Another similar measure that is more appropriate for measurement in animals, is capillary transport reserve. In White’s study of Yucatan mini-pigs, capillary transport reserve increased even more dramatically than coronary blood flow. Whereas blood flow increased by 22%, capillary transport reserve increased by almost 60%

3) Increased capacity for metabolizing fuel to produce energy. One of the metabolic adaptations that occurs with training is an increase in the ability to transport lactate from the blood stream into the heart. In general heart muscle works in the aerobic zone, but it can nonetheless use lactate (produced for example by skeletal muscle) as fuel. The transport system that moves lactate across the sarcolemma (cell membrane) of heart muscle responds well to training (Bonen, Eur J Appl Physiol, 2001, 86, 6-11) It seems to me that this might be a very valuable adaptation for the long distance runner. If blood glucose reserves begin to fall in the later stages of a long run in the upper aerobic zone, the capacity to utilize the lactate that has accumulated in the blood following extrusion from skeletal muscle, should at least ensure that the heart has an adequate supply of fuel.

White and Bloor’ study of Yucatan mini-pigs demonstrated that a training program similar to that which might be recommended for base building prior to a half marathon or marathon program (though perhaps a little monotonous for my own taste) resulted not only in increased small blood vessels number and diameter, but also increased capillary transport reserve and cardiac muscle hypertrophy. However, not all types of training produce the same profile of benefits for the heart. In a future post, I will examine what little evidence there is regarding the optimum training program for achieving improvements in each of the different aspects of cardiac fitness.

Is heart muscle or leg muscle the limiting factor?

Both heart muscle and leg muscles play a crucial role in running. The function of both of these types of muscle can be enhanced by training. This raises two major questions:

1) When is the function of the heart the factor that limits our performance and when is skeletal muscle the limiting factor?

2) Are different training regimes required for optimal development of heart and skeletal muscle?

In my next few postings I intend to examine what evidence there is that might help answer these questions, but first is of interest to consider a few similarities and differences between the roles of these two types of muscles.

The heart must beat for life

One of the crucial differences is that the heart must continue to beat throughout life, whereas skeletal muscle is called upon to act for relatively limited periods of time, ranging from a few minutes in middle distance races to a few hours in long distance events such as the marathon. This difference in function necessitates some differences in the options for use of fuel, though during long distance races, both types of muscle rely largely on aerobic metabolism and therefore on an adequate supply of oxygen. From the point of view of the runner, the crucial issue is that a torn skeletal muscle is a frustrating inconvenience whereas serious disruption of the heart is potentially fatal. While the evidence suggests that regular exercise decreases risk of heart attack, unfortunately, there is also clear evidence that very demanding exercise, such as running a marathon, is associated with an increased risk of heart attack within the following 24 hours (Journal of the American College of Cardiology, vol 28, pp 428-431, 1996). In most cases, post mortem examination reveals that such deaths are due to pre-existing abnormality of the heart, especially abnormalities of the coronary vessels that deliver blood to the heart muscle .

The heart is a complex pump

Another crucial difference is in the complexity of the function and therefore on the susceptibility to disruption of that function. In general a skeletal muscle is simply required to either to shorten to achieve the required movement of the bones to which it is attached and thereby flex or extend a joint (i.e concentric contraction), or to resist a forcible extension of the muscle and thereby limit or slow flexion or extension of a joint (eccentric contraction). In fact the amount of tension generated within the muscle must be controlled quite exquisitely if the action of the muscle is to be efficient. Nonetheless the essential requirement is simply to exert the required amount of force along the long axis of the muscle.

In the case of the heart, the required action is much more complex. The heart is a four chambered pump: there are two atria and two ventricles. The right atrium collects the blood that is returned from the tissues of the body (via the two large draining veins known as the inferior and superior vena cava) and transfers it via a valve into the right ventricle. The right ventricle pumps the blood to the lungs to replenish its supply of oxygen and dispose of its burden of carbon dioxide. The freshly oxygenated blood from lungs is collected in the left atrium and transferred into the left ventricle from whence it is pumped into aorta, and thence distributed to the body tissues. This pumping action requires a well coordinated contraction of the four chambers with very precise timing. The timing is controlled by a wave of electrical activity that spreads through the muscular walls of the chambers, from a starting point known as the sinoatrial (SA) node in the wall of the right atrium. The spreading electrical signal is transmitted from the atrial walls to the ventricles via the atrio-ventricular (AV) node.

Left to its own devices, the SA node would fire regularly at a certain base frequency. However various influences including levels of circulating adrenaline and also input from the autonomic nervous system, adjust the rate of firing of the SA node according to the body’s needs.

Fibrillation

While the SA node is the usual site from which the spreading electrical impulse that produces contraction is initiated, any heart muscle cell can fire spontaneously, though usually at a rate lower than that of the SA node. If for some reason, such as irritation of the muscle cells by toxins released following damage arising from inadequate blood supply via the coronary arteries, muscle cells other than the SA node fire prematurely and the orderly spread of contraction is disrupted. The wall of the relevant chamber now flaps ineffectually (fibrillation). Provided this fibrillation is confined to the atria, enough blood to fulfill the body’s basic needs is usually drawn into the ventricles as they relax following the previous contraction. Thus the ventricles fill sufficiently to allow ejection of enough blood to meet essential needs provided a ventricular contraction is initiated. In most instances of atrial fibrillation, the AV node takes over the role of initiating an orderly ventricular contraction. Perhaps the person might feel a bit dizzy, but the outcome is not catastrophic. However, if the fibrillation spreads to the ventricles, effective pumping to the tissues of the body cannot occur and the outcome is fatal unless rhythmic contraction is restored very rapidly. Thus ventricular fibrillation is a type of ‘heart attack’ that results in sudden death

Benefits of training

Training might potentially have several benefits to the heart. First of all, there is clear evidence that in heart muscle, as in skeletal muscle, exercise results in increased density of capillaries distributing blood from the coronary arteries to the heart muscle. This would be expected to improve oxygen supply and reduce the risk of heart attack However, as in the case of skeletal muscle, the benefits of training are achieved via compensation for microscopic damage due to the stress of vigorous exercise.

When skeletal muscle is damaged various proteins, including the enzyme creatinine kinase, are released into the blood stream. Following prolonged vigorous exercise, such as running a marathon, blood levels of creatinine kinase rise markedly, indicating appreciable muscle damage. Similarly, when heart muscle is damaged various proteins are released into the blood stream. One characteristic marker of heart muscle damage is a high level of the protein troponin. Elevated troponin levels are observed after prolonged vigorous exercise.

Thus, the mechanism by which the density of capillaries supplying heart muscle is increased, thereby reducing long term risks of a heart attack, appears to involve at least some degree of microscopic damage. Unaccustomed strenuous exercise potentially creates an appreciable short term risk. Hence it is necessary to build up training volume gradually so that the heart gradually accommodates to the demands placed upon it.

As discussed above, in contrast to the risks of damage to skeletal muscle when the athlete might suffer a frustrating but temporary interruption of training, the risks associated with damage to heart muscle are potentially more catastrophic. On the other hand, because the normal demands of an active life style ensure that the heart is continually exercised, it is usually safe for an individual who has been leading an active lifestyle to build up training volume and intensity at a moderate rate. In very rare instances, congenital abnormalities might result in the development of abnormal electrical conducting pathways in the heart, creating the risk of sudden and tragic heart attack in an otherwise fit young person.

Hypertrophy

Development of capillaries that improve the distribution of blood from the coronary arteries to the heart muscle is not the only beneficial effect of training. It is also possible to increase the size of the heart. There are two principle types of hypertrophy: an increase in the diameter of the ventricles which leads to increased stroke volume; and an increase in the thickness of the walls of the ventricles, which can produce more powerful contraction. Increase in ventricular diameter and stroke volume will result in an increase in aerobic capacity – the ability to deliver oxygen to body tissues, including skeletal muscle, and hence is likely to improve distance running performance.

Various different training strategies have been proposed to maximize the enhancement of stroke volume. I will discuss these training strategies in a future post.