Unexplained exertional dyspnea caused by low ventricular filling pressures: results from clinical invasive cardiopulmonary exercise testing

[Kyla]

This isn't about ME, but some of the patients had POTS, and this is discussed in the context of exercise testing. Thought the results might be of interest to some here.
I have pulled out one of the relevant sections and quoted it (below the abstract)

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4860548/
(Open Access)

Unexplained exertional dyspnea caused by low ventricular filling pressures: results from clinical invasive cardiopulmonary exercise testing
William M. Oldham,

1,2,3 Gregory D. Lewis,3,4 Alexander R. Opotowsky,2,3,5 Aaron B. Waxman,1,2,3 and David M. Systrom1,2,3
Author information ► Article notes ► Copyright and License information ►

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Abstract
To determine whether low ventricular filling pressures are a clinically relevant etiology of unexplained dyspnea on exertion, a database of 619 consecutive, clinically indicated invasive cardiopulmonary exercise tests (iCPETs) was reviewed to identify patients with low maximum aerobic capacity (V̇o2max) due to inadequate peak cardiac output (Qtmax) with normal biventricular ejection fractions and without pulmonary hypertension (impaired: n = 49, V̇o2max = 53% predicted [interquartile range (IQR): 47%–64%], Qtmax = 72% predicted [62%–76%]). These were compared to patients with a normal exercise response (normal: n = 28, V̇o2max = 86% predicted [84%–97%], Qtmax = 108% predicted [97%–115%]). Before exercise, all patients received up to 2 L of intravenous normal saline to target an upright pulmonary capillary wedge pressure (PCWP) of ≥5 mmHg. Despite this treatment, biventricular filling pressures at peak exercise were lower in the impaired group than in the normal group (right atrial pressure [RAP]: 6 [IQR: 5–8] vs. 9 [7–10] mmHg, P = 0.004; PCWP: 12 [10–16] vs. 17 [14–19] mmHg, P < 0.001), associated with decreased stroke volume (SV) augmentation with exercise (+13 ± 10 [standard deviation (SD)] vs. +18 ± 10 mL/m2, P = 0.014). A review of hemodynamic data from 23 patients with low RAP on an initial iCPET who underwent a second iCPET after saline infusion (2.0 ± 0.5 L) demonstrated that 16 of 23 patients responded with increases in Qtmax ([+24% predicted [IQR: 14%–34%]), V̇o2max (+10% predicted [7%–12%]), and maximum SV (+26% ± 17% [SD]). These data suggest that inadequate ventricular filling related to low venous pressure is a clinically relevant cause of exercise intolerance.


Dyspnea on exertion is a common presenting symptom with a broad differential diagnosis. Often the etiology remains unclear despite a thorough clinical and laboratory investigation.1,2 Cardiopulmonary exercise testing (CPET) may assist in the diagnostic evaluation by defining the degree of impairment in maximum aerobic capacity (V̇o2max), identifying the limiting organ system (e.g., heart vs. lung), and providing clues as to more specific pathophysiology. When CPET is coupled with invasive hemodynamic monitoring using radial and pulmonary arterial catheters (i.e., invasive CPET [iCPET]), the presence of peripheral and central cardiovascular abnormalities can be better characterized through direct measurements of systemic and pulmonary vascular pressures and systemic and mixed venous oxygen content as well as precise estimation of cardiac output (Qt).3 For example, these measurements have been used to characterize the exercise-induced increases in ventricular filling pressure and pulmonary arterial pressure in patients with heart failure4-8 and pulmonary arterial hypertension,9 respectively. Despite a detailed hemodynamic and metabolic evaluation, nearly 10% of symptomatic patients studied with iCPET in our laboratory had low V̇o2max and low maximum Qt (Qtmax) without a clearly identified cause.

During the normal exercise response, sympathetic stimulation and vagal withdrawal increase heart rate (HR), contractility, and mean systemic pressure. Increased respiratory efforts and vigorous limb skeletal muscle contractions also enhance venous return to the heart. Together, these responses increase stroke volume (SV) through the Frank-Starling mechanism. In this study, we tested the hypothesis that failure of these mechanisms to increase cardiac preload during exercise, as evidenced by persistently low ventricular filling pressures, may be the primary limitation of Qtmax in an undiagnosed population of patients with unexplained exercise intolerance.

Discussion of the results for POTS patients:

Presuming adequate intravascular volume and similarly functioning respiratory and muscle pumps, the etiology of inadequate venous return may be a consequence of impaired venoconstriction of capacitance vessels in the impaired population. Indeed, the observation that 10 patients in the impaired group had abnormal neuroendocrine testing with evidence of POTS (5 cases), adrenal insufficiency (3 cases), or autonomic neuropathy (2 cases) supports this hypothesis. POTS is characterized by orthostatic tachycardia without significant hypotension.14 Yet these patients often experience presyncope, palpitations, and exercise intolerance that resolve with lying supine. The pathophysiologic basis of POTS is unclear, and the diagnosis itself likely reflects a conglomeration of different mechanisms. A report demonstrated that POTS patients have reduced left ventricular mass and decreased blood volume, leading to low peak SV and Qt with compensatory increases in HR.15 The invasive hemodynamic profile of the 5 POTS patients in this study confirms a significantly reduced peak SV compared to normal patients, consistent with a previous study.16 We further show that POTS patients had persistently low RAP despite receiving an average of 1 L of normal saline before the test, suggesting that venous capacitance is the issue rather than total intravascular volume. Other studies have also suggested that inadequate peripheral vasoconstriction,17cardiac sympathetic dysautonomia,18 and autoimmune autonomic neuropathy19 may contribute to symptoms of POTS. All POTS patients in this study had improvement in subjective exercise tolerance with medical therapy, 4 with β-adrenergic receptor antagonists and 1 with midodrine, in addition to increased fluid intake, compression stockings, and monitored exercise training. These observations can likely serve as a starting point for additional investigations into the mechanistic underpinnings of the exercise limitation in patients with preload insufficiency.

Interestingly, impaired patients had decreased systemic oxygen extraction normalized to [Hb], as compared to normal ones (0.81 ± 0.12 vs. 0.87 ± 0.09, P = 0.04), which is consistent with abnormal blood flow distribution to metabolically inactive vascular beds (e.g., impaired splanchnic vasoconstriction with exercise), shunting past oxidative muscle fiber capillary beds, or intrinsic mitochondrial dysfunction. Regardless of the etiology, this finding is suggestive of generalized circulatory dysregulation as a component of the pathogenesis of exercise intolerance in impaired patients. Anecdotally, several of these patients report a severe illness before symptom onset, in many cases occurring 1 year or more before their evaluation, suggesting that an infectious or inflammatory etiology may contribute. In addition, structural limitations to venous return, such as inferior vena cava thrombosis, should be considered in the differential diagnosis.

Notably, the improvement in V̇o2max after volume administration in the sequential-testing cohort was less striking than the improvement in Qtmax. This is similar to the recent noninvasive study of POTS patients undergoing an intravenous fluid challenge.20 Our data indicate that this is entirely due to the effects of dilutional anemia on oxygen extraction (Fig. 4), as the Ca-O2/[Hb] ratio did not change after volume administration in the sequential-testing cohort (+1 ± 9%, P = 0.5). Human studies demonstrate a decrease in the V̇o2max of exercising leg muscle after isovolemic reduction in [Hb], two-thirds of which is attributable to reduced diffusion of oxygen;21 while the precise mechanism is unknown, oxygen delivery may depend on intracapillary red blood cell spacing, changes in oxygen dissociation rates, or increased red blood cell flow heterogeneity.21,22 This suggests that therapeutic interventions to increase intravascular volume (e.g., oral hydration, fludrocortisone, salt tabs) may be less effective than therapies directed at vascular tone (e.g., midodrine, pyridostigmine). Indeed, pyridostigmine has shown promise in patients with POTS, particularly when associated with antecedent viral infection or secondary to an autoimmune disorder.23,24 The role of these medications in treating patients with exercise intolerance due to abnormal venous return, as described here, is a promising area for future investigation.

 

[JaimeS]

Yeah, I saw this too -- or else a nearly identical article -- and starting looking up incomplete filling of ventricles. It was an interesting path to travel down.

 

[ryan31337]

Hard work to read but really interesting. The take away point of this study according to the summary I saw was that it is further proof that POTS is not deconditioning, with a difference shown in right atrial pressures between POTS and deconditioned individuals, suggestive of impaired venoconstriction.

I thought all that was well understood already, considering the standard treatment choices for POTS (midodrine etc.) but I guess its not well proven and that's why they're used off-label still...

 

[JaimeS]

I thought all that was well understood already, considering the standard treatment choices for POTS (midodrine etc.) but I guess its not well proven and that's why they're used off-label still...

I've had this same experience often, @ryan31337 ... what the patient community and the doctors who work closely with them 'know' is often not proven in the medical lit.... yet.

 

[anciendaze]

Please note that this was a retrospective study done on hundreds of patients who had invasive CPET for reasons considered valid clinical indications. If anyone is aware of a single ME/CFS patient who has had iCPET I would like to know about them.

These patients would meet a cardiologist's definition of exercise intolerance because they exhibited dyspnea during exercise, which most of us do not. CPET testing of ME/CFS patients typically checks for pulmonary problems first, and these patients would be referred to different doctors. Exactly what happens to them then is a good question.

One cohort of these patients was given IV saline, presumably to correct possible hypovolemia, which also shows up in ME/CFS. Another cohort was tested both without and with this preloading to see how it affected results. Their ability to benefit from this, in terms of increased stroke volume, appeared to be reduced.

We have no idea of what the patients experienced in the days after testing because that is typically not a concern for cardiologists. We don't know if they resembled ME/CFS patients in having PEM/PENE. I suspect they did.

Problems seen in ME/CFS include endothelial dysfunction, which might well be responsible for problems with venous return. We tend to think of the heart as a pump and vascular systems as inactive pipes, but this underestimates the amount of activity, particularly in tiny blood vessels where it is hard to observe with traditional cardiovascular measurements. Anyone who has experienced vasovagal syncope should know behavior of blood vessels is quite active. I am now curious about pulmonary capillary wedge pressure in ME/CFS patients.

This paper reported decreased stroke volume in patients, which also happens in ME/CFS. We don't know about pressures requiring invasive tests because these are not done unless there is a perceived risk to life, which is not there in ME/CFS.

What I miss most here is any data on the ability of heart muscle fibers to relax, as shown best by IVRT. I would predict that this was longer than in healthy patients. Such impairment could point to mitochondrial dysfunction and viral or autoimmune disease.

 

[JollyRoger]

@anciendaze
@JaimeS
@ryan31337
I know it's an old thread but may I ask you a question.
Could it be that mitochondrial dysfunction is not the cause but a side effect of the low blood volume?
Check the picture....


It's because I had a gradual onset of me cfs and had several checkups (already checking my heart for years).
In every echo my heart got smaller and the vena cava diameter (is used to check the blood volume and is increased in heart failure) also got smaller.
I also noticed in the beginning that after drinking vast amounts of water i was free of symptoms.

 

[JaimeS]

Low blood volume is another one of those 'all ME/CFS doctors know' but it's not well-documented. Looking into this myself actually.

 

[ryan31337]

If anyone is aware of a single ME/CFS patient who has had iCPET I would like to know about them.

Hi @anciendaze,

I had a PR member inbox me recently who had abnormal CPET tests similar to mine - he went on to have an iCPET under care of Dr Systrom. I'll message them and see if they're happy to share details with everyone.

I am currently on the waiting list for another test, which I know only as 'EPR' - I got this from being copied into correspondence between my POTS cardio & the consultant that runs the complex physiology testing lab. I wonder if this might be Exercise Pressor Reflex? Seems to be pertinent in my case as I have episodes of hypertension after exertion/orthostasis, low AT/VT and fit squarely in the hyperadrenergic POTS camp.

This is quite an interesting read: http://ajpheart.physiology.org/content/309/9/H1440
It discusses the practise of artificially restricting blood flow to muscles whilst exercising, in order to accumulate metabolites like lactic acid at lower intensity exertion than would normally be required - apparently this environment can lead to greater muscle growth and strength. But it runs the risk of exaggerated sympathetic nervous system activation....sounds familiar huh

 

[JollyRoger]

Blood flow restriction training - some guys in my gym did it (many moons ago)
They loved the burning...... and I have it 24h a day now.....WWWAAAAHHHHH!


That would explain the PEM because low ATP was also found in depression and they have no problems post-exercise.

 

[anciendaze]

@JollyRoger,

I think episodic hypovolemia is part of dysautonomia. Drinking lots of water only temporarily deals with part of this, since it causes a drop in concentration of electrolytes like sodium or potassium. This has also caused me to pass out. Now, before I go out, I not only drink water, but also take a SaltStick capsule, as if I were going to do heavy exercise. You have to take this before you get in trouble because absorption of electrolytes through the stomach is slow.

The problem with ATP is not how much, but when and where it is released. Some tests show increased ATP, but not from the cell's own mitochondria. I suspect this is from a standard response to localized hypoxia, after dropping the O2 they carry, erythrocytes will dump ATP in regions that remain hypoxic. This enables local cells to survive an hypoxic episode through localized anaerobic metabolism. ATP is also a major biochemical signal affecting vasoconstriction, etc.

This goes along with evidence of low anaerobic threshold during exercise. One problem with testing for this is that some cells in the body can be in anaerobic metabolism while most are not. Tests are able to measure VO2max, but we have little to show localized anaerobic activity except accumulation of lactates.

@ryan31337,

I'll be interested in any results of iCPET. I have no experience with EPR.

My own problem seems to fit in with neurally-mediated hypotension, not hypertension. However, if you call me in 5 hours before minor surgery, then leave me sitting in the waiting room for that time, when you finally prep. me you will find systolic bp of 160. If I had not been straining to keep functioning, I would have passed out. This is typically interpreted as hypertension, and the prescription would be drugs to lower mean bp. If they did this, I would frequently be unable to stand up.

I'm afraid this is a common practice with elderly patients, leaving them bedbound. My first episodes began in my teens and 20s, but now I fit the elderly profile doctors expect. I've regularly seen elderly people have episodes of syncope 2 to 3 hours after taking bp medication. Repeated episodes of cerebral hypoperfusion are likely to result in general neurological deterioration, but the medication is justified as avoiding a risk of stroke, which is life-threatening.

The problem is not "too high" or "too low", it is poor regulation of bp. No simple pill treats that.

 

[Gingergrrl]

This was a fascinating thread and I just discovered it. In my case, I have autoantibodies where my lung tissue itself is normal but my respiratory muscles (and other muscles) are weakened. Because of this, I cannot really use 02 saturation or arterial blood gas testing to accurately detect the level of dyspnea that I experience.

I also have POTS since 2013 (confirmed 100% by TTT at Stanford). My doctor now considers me to have "Autoimmune POTS" b/c of autoantibodies that affect the beta adrenergic receptors (in addition to the ones that cause muscle weakness).

I have never found fluid loading to be of any help and my attempt at IV saline in 2014 led to flash pulmonary edema and being rushed to the ER. I also tried Mestinon that same year and had a horrible reaction. But I get great benefit from Atenolol and Midodrine. And I have had the greatest benefit from high dose IVIG, which definitely does cause a temporary increase in fluid volume, but I do not believe that this is the mechanism in which it is helping me vs. that it is temporarily knocking down the pathogenic autoantibodies (even though they keep coming back ).

I have never had a CPET test but I am so curious if it would accurately reflect my situation? The article says it can distinguish between cardiac and pulmonary causes of dyspnea, but can CPET assess for respiratory muscle weakness as the cause of dyspnea if caused by autoantibodies? I do not know the answer myself but was curious @JaimeS what you think since you are actively studying and researching this stuff and you have a solid grasp of it all (unlike me )!

These patients would meet a cardiologist's definition of exercise intolerance because they exhibited dyspnea during exercise, which most of us do not.

I found this quote very interesting from @anciendaze because I assumed that everyone with ME/CFS would have dyspnea during actual exercise like a CPET test but this now makes me think that I am wrong. If most CFS patients would not have dyspnea during a CPET test (and this has been shown in studies), then I know with absolutely certainty for the first time, that CFS is not my diagnosis. I would be gasping for air with chest pain before the first minute of the test was done (or at least I would have been prior to eleven months of IVIG). Now I cannot say for sure if I could last one minute (it is possible?) but I would definitely have dyspnea even if the test would no longer send me to the ER.

 

[JollyRoger]

Regarding my idea of low blood volume causes mitochondrial dysfunction I found this in a paper of Julia Newton:

Additionally, it is also possible that reduced vascular runs off (related to autonomic dysfunction), resulting in decreased vascular flow into and out of the muscle following exercise which may have an effect on O2 delivery, potentially limiting the function of the three-enzyme complex pyruvate dehydrogenase complex (PDC) [91].
{>>>>>>>
PDC/PDH were the inhibited enzymes that they found in Norway.

Hypoperfusion of the brain, mitochondrial dysfunction through low 02 , peeing a thousand times a day.... would be a good explanation for all these stuff

 

[JaimeS]

can CPET assess for respiratory muscle weakness as the cause of dyspnea if caused by autoantibodies? I do not know the answer myself but was curious @JaimeS what you think since you are actively studying and researching this stuff and you have a solid grasp of it all (unlike me )!

So plain old CPET would not be able to determine cause of dyspnea, IMO.

However, iCPET:

iCPET at UPMC will entail breath-by-breath analysis of ventilatory gas exchange and invasive measurement of pulmonary vascular and cardiac function in association with upright cycle ergometer and ECG exercise testing.

Patients undergoing iCPET studies will have a pulmonary artery and radial artery catheter placed for the invasive measurements.

With the iCPET modality cardiac output, pulmonary artery pressures, multiple ventilatory indices, systemic pressures and ECG variables are simultaneously assessed during a progressive intensity exercise provocation.

iCPET adds significantly to the diagnostic sensitivity. In particular iCPET testing can delineate disease states related to pulmonary arterial, pulmonary venous, cardiac valvular, loading dynamics, autonomic, and skeletal muscle pathophysiologies that limit exercise capacity.

Boldface mine -- from http://pulmvasc.pitt.edu/patient-care/icpet/ -- looks like it can do that!

If most CFS patients would not have dyspnea during a CPET test (and this has been shown in studies), then I know with absolutely certainty for the first time, that CFS is not my diagnosis.

Hmm. Well, I've all the symptoms for ME/CFS as per CCC (almost literally ALL of them) -- and I had dyspnea straight afterwards. They had to support me off the bike, doing my usual gasping for air. I swore "this passes, just wait..." I said I didn't need oxygen, but they kept asking me until I said 'yes' (I think they needed my permission to administer, since I was conscious.) So.

Also, it's only second-day CPET that is 'supposed' to show abnormalities; but my lactic acid was several-fold times higher than normal. The exercise physiologist told me there was no way my response was due to deconditioning.

We all have mechanisms behind our illness and yours and mine may be a tad atypical. However, the dx still holds, IMO.

-J

 

[Gingergrrl]

So plain old CPET would not be able to determine cause of dyspnea, IMO.

That was my understanding, too, but I was not certain.

However, iCPET:

Interesting but it sounds very invasive . Has anyone on PR ever had an iCPET test?

Hmm. Well, I've all the symptoms for ME/CFS as per CCC (almost literally ALL of them) -- and I had dyspnea straight afterwards. They had to support me off the bike, doing my usual gasping for air. I swore "this passes, just wait..." I said I didn't need oxygen, but they kept asking me until I said 'yes' (I think they needed my permission to administer, since I was conscious.) So.

Okay, then you would be more like me! This is what I thought except for when I read AD's quote above that most PWC's would not have dyspnea w/exercise, it confused me.

We all have mechanisms behind our illness and yours and mine may be a tad atypical. However, the dx still holds, IMO.

I guess the bottom line is that I remain confused if ME/CFS is my diagnosis or not but I guess it really does not matter as much as I would like to know for sure!

 

[JaimeS]

I guess it really does not matter as much as I would like to know for sure!

It only matters if another diagnosis would give you more treatment options...

 

[ryan31337]

The article says it can distinguish between cardiac and pulmonary causes of dyspnea, but can CPET assess for respiratory muscle weakness as the cause of dyspnea if caused by autoantibodies?

Regular CPET can certainly assess for respiratory muscle weakness and is often combined with pulmonary function & blood gas tests to guide analysis. I think the most obvious indication of a lung or neuromuscular disease is that end tidal CO2 does not decrease towards the end of the test. They'll also be indications from your breathing patterns & maximum work rate. Its just suggestive of a problem there though, its unlikely to determine what the underlying pathology is.

I understand that the big benefit of iCPET to us is its ability to differentiate between issues of oxygen utilisation e.g. mitochondrial myopathy, and oxygen delivery problems e.g. preload failure due to dysautonomia. A non-invasive CPET would simply show reduced O2 pulse, but O2 pulse depends on both stroke volume and the a-v O2 content difference. Stroke volume is reduced in dysautonomia, a-v O2 content difference is decreased in MM. So by having arterial and mixed-venous catheters in place to measure the venous PO2 and the a-v O2 content difference you can determine which is the biggest limitation.

There's an outside chance some of us with abnormal day 1 CPETs have MM, but its more likely to just be reduced stroke volume on orthostasis/exercise (normal at rest). This is diagnosed by Dr Systrom as preload failure, which he considers a result of dysautonomia.

I assumed that everyone with ME/CFS would have dyspnea during actual exercise like a CPET test but this now makes me think that I am wrong. If most CFS patients would not have dyspnea during a CPET test (and this has been shown in studies), then I know with absolutely certainty for the first time, that CFS is not my diagnosis. I would be gasping for air with chest pain before the first minute of the test was done (or at least I would have been prior to eleven months of IVIG). Now I cannot say for sure if I could last one minute (it is possible?) but I would definitely have dyspnea even if the test would no longer send me to the ER.

In between relapses I had years of good physical function and normal (immediate) response to exercise, no dyspnoea just PEM the next day. Its only during relapses, when i've had significantly worsened OI, that dyspnoea has been a problem.

I would hazard a guess that Day 1 CPET abnormalities are likely linked to significant autonomic dysfunction. Which in my experience is a lot more disabling and less manageable than the energy recovery/PEM issues associated with mild/moderate ME, so would perhaps get chalked up as primary POTS or whatever and maybe be excluded from ME studies?

 

[JollyRoger]

We know that Dr scheibenbogen found autoantibodies in some cfs patients... one of them is the autoantibody against β2-adrenergic receptors.

Now I found this:

During exercise, α1-adrenergic receptors in active muscles are attenuated in an exercise intensity-dependent manner, allowing the β2-adrenergic receptors which mediate vasodilation to dominate.

And a study:

Physical exercise, β-adrenergic receptors, and vascular response

Maybe cfs is an autoimmune disease against vessel receptors.

The vessels should be an active "organ" to pump the blood.

Anyone tried swimming (water pressure maybe helps a bit?)????

 

[Binkie4]

[ blood volume is another one of those 'all ME/CFS doctors know' but it's not well-documented. Looking into this myself actually./QUOTE]
@JaimeS

Just got in from a cardiology appointment this morning with Consultant and medical student present for review of mitral valve prolapse, primary symptom dyspnea.

I was asking about low blood volume and its effects. Cardio didn't know and said blood volumes had not been on syllabus in his training nor are they currently which his student confirmed. This was for ordinary people so what hope do we have?

Who decides what is important for doctors to know?

EDIT: apologies for all yellow. It's the second time it's done that. Will work it out when energy returns.

 

[JaimeS]

@Binkie4 -- Find the [ / Q U O T E .] If it's at the end, move it to where you want the quote to stop. It looks like you have [ blood volume is another one of those 'all ME/CFS doctors know' but it's not well-documented. Looking into this myself actually.../....QUOTE..]

That red bracket needs to move here:

blood volume is another one of those 'all ME/CFS doctors know' but it's not well-documented. Looking into this myself actually.[... /.QUOTE..]

LOL trying not to make the coding actually work by doing weird stuff!

Generally, tradition decides what it is best for doctors to know. The CBC in the US (complete blood count) contains a limited number of markers for a limited number of disorders, meaning that people with diseases discovered earlier on tend to be able to find out what's the matter with them swiftly, while people with disease identified or better-described in the modern era are usually left flailing about in medical limbo for years as physicians wonder which test to try, next. In universities, the education of doctors often lags decades behind, taught by people who feel they know all they need to know about medicine and have not kept abreast of the latest findings in their field -- or, to be fair, people who have to publish papers to survive and also be a university lecturer, which leaves them little time for following ideas they are not working on, themselves.

Our only hope so far is self-education. I am working hard and so are some other devoted scientists on your side, but meanwhile it's important to find out everything that you can, yourself.

 

[Binkie4]

Thank you @JaimeS .

I will work on your quotes explanation but until yesterday, I thought I had it sussed!

It does seem strange that UK medical training even today contains nothing about blood volume for a cardiologist. Nor does it cover the haemorheological aspects. As you said ( almost)- do it yourself!