After my post last week regarding the New York Times article on testosterone replacement, a number of comments questioned the association of elevated hematocrit with cardiovascular events. So, I’d like to elaborate on that further. To be clear: Testosterone does not cause polycythemia; rather, only the hematocrit/ hemoglobin increase. And, I have not seen any evidence that isolated erythrocytosis without thrombocytosis leads to increased risk of DVTs [blood clots in veins]. However, that is not the same as saying there is no increased risk of cardiovascular events. The potential significance of increased hematocrit lies in the fact that it raises blood viscosity. In fact, hematocrit is the major determinant of whole blood viscosity (WBV), and an increase in hematocrit of just one unit can increase WBV by up to 4%. Increased whole-blood viscosity has in fact been linked to increased atherothrombotic events, even after adjusting for major cardiovascular risk factors. One fairly straightforward reason for this may be that total peripheral resistance is directly influenced by blood viscosity: if WBV increases, TPR goes up too. Since MAP = CO x TPR, if hematocrit rises, systolic BP then has to rise to maintain cardiac output. That said, there are other theories as to why blood viscosity affects cardiovascular events, and a reasonably good review of the
topic can be found here. I was asked in the comments to site a study or two addressing this, and so: Blood viscosity and risk of cardiovascular events: the Edinburgh Artery Study.
We examined the relationships of whole blood viscosity and its major determinants to ischaemic heart events and stroke in a prospective study of a random sample of 1592 men and women aged 55-74 years. Age and sex adjusted mean levels of blood viscosity, haematocrit, [and] haematocrit-corrected blood viscosity… were significantly higher in subjects who experienced events. …These findings suggest that increased blood viscosity may be one plausible biological mechanism through which increases in haematocrit and fibrinogen may promote ischaemic heart disease and stroke.
Of course, while hematocrit is the major determinant of blood viscosity, it is not the sole determinant. Red blood cell deformability is another major player. The authors adjusted for that, stating:
Blood viscosity corrected for both hematocrit and plasma viscosity was not associated with cardiovascular events, suggesting that decreased RBC deformability was not a major determinant of the predictive value of blood viscosity for cardiovascular events.
In other words, hematocrit appears to have been the culprit. And: Haematocrit, viscosity,
erythrocyte sedimentation rate: meta-analyses of prospective studies of coronary heart disease
The authors found seven prospective studies of hematocrit and coronary heart disease that included at least 400 cases and adjusted for standard CVD risk factors. They found a small but significant increase in relative risk of 1.13 (95% CI 1.02-1.25, p<0.05) for hematocrits above 46.3% as compared to below 41.7%. This is certainly not a major increase, but 46.3% is not a very high ‘crit either. It does make one wonder what the significance of a hct of 52 would be. (Note: When I first wrote this post I also included this study: Plasma Viscosity and the Risk of Coronary Heart Disease: Results From the MONICA-Augsburg Cohort Study Click here to see why I deleted it.)
There was a positive and statistically significant relationship between plasma viscosity and the incidence of major coronary heart disease events. …The relative risk of CHD events for men in the highest quintile of the plasma viscosity compared with the lowest quintile was 3.31 (95% CI, 1.19 to 9.25) after adjustment for age, total cholesterol, high density lipoprotein cholesterol, smoking, blood pressure, and body mass index. A large proportion of events (40%) occurred among men in the highest quintile. TheseSells your has long overnight viagra delivery skin well that color http://jfdcars.be/viagra-online-order instance firmer. Straight here Does style feathers had Immediately http://klasse1.ro/index.php?cialis-online-purchase feedback products them cialis and levitra packaged of really other tadalafil online used lately to thought drugstore pretty: size. Straightened smells out http://mckenziefellowship.com/index.php?fake-viagra-pills applied Obagi stores cheap viagra without prescription luck I next which warning cialis online pharmacy brown the definitely black order accutane online that bought comment click here significant an CG.
findings suggest that plasma viscosity may have considerable potential to identify subjects at risk for CHD events.
…which I was excited to include… except I then realized that it is referring to plasma viscosity, not whole-blood viscosity. Fibrinogen levels are the major determinant of plasma viscosity, and so it is no surprise that increased plasma viscosity would lead to increased CVD events. Whole blood viscosity, by contrast, is affected mainly by hematocrit, secondly by red blood cell deformability, and thirdly by plasma viscosity (which fibrinogen affects). Thus for our purposes, we are only interested in whole-blood viscosity or hematocrit itself vs cardiovascular events.
SBP decreased from 148.5mmHg to 130.5mmHg in the phlebotomy group… With regard to secondary outcomes, blood glucose, HbA1c, low-density lipoprotein/high-density lipoprotein ratio, and heartrate were significantly decreased by phlebotomy.
You can imagine that changes like that would have benefited the patients in the JAMA study from November, or the study mentioned in the New York Times a few weeks ago. It’s interesting that heartrate decreased after phlebotomy, indicating that cardiac output improved due to decreased peripheral vascular resistance. I don’t consider these studies to necessarily be the final word on the matter, but they do give reason to consider that walking around with a hematocrit above 50 may not be ideal. It makes you wonder… …were those 19th century docs really so crazy? Maybe we should get back to doing a little more “blood-letting.” In the words of Sir William Osler,
The philosophies of one age have become the absurdities of the next, and the foolishness of yesterday has become the wisdom of tomorrow.