I plan on using this thread to capture comments/discussion on secondary erythrocytosis from TRT (Hct/viscosity) and cardiovascular risk. Alot of my previous comments/question/posts have been spread over a number of other’s threads.
In particular, I’ve seen a number of comments (even interviews with Experts) trying to rationalize running Hct high because there’s plenty of people at high altitude that do just fine with high Hct. Truth is there are a fraction of these folks that suffer significant symptoms and they are a great group to study and see how excess blood viscosity manifests in increased cardiovascular risk:
Excessive erythrocytosis (EE; hemoglobin concentration [Hb] ≥21 g/dL in adult males) is associated with increased cardiovascular risk in highlander Andeans. We sought to quantify shear stress and assess endothelial function via flow-mediated dilation (FMD) in male Andeans with and without EE. We hypothesized that FMD would be impaired in Andeans with EE after accounting for shear stress and that FMD would improve after isovolemic hemodilution. Brachial artery shear stress and FMD were assessed in 23 male Andeans without EE (age: 40±15 years [mean±SD]; Hb<21 g/dL) and 19 male Andeans with EE (age: 43±14 years; Hb≥21 g/dL) in Cerro de Pasco, Peru (4330 m). Shear stress was quantified from Duplex ultrasound measures of shear rate and blood viscosity. In a subset of participants (n=8), FMD was performed before and after isovolemic hemodilution with blood volume replaced by an equal volume of human serum albumin. Blood viscosity and Hb were 48% and 23% higher (both P <0.001) and FMD was 28% lower after adjusting for the shear stress stimulus ( P =0.013) in Andeans with EE compared to those without. FMD was inversely correlated with blood viscosity ( r 2=0.303; P<0.001) and Hb ( r 2=0.230; P =0.001). Isovolemic hemodilution decreased blood viscosity by 30±10% and Hb by 14±5% (both P <0.001) and improved shear stress stimulus-adjusted FMD from 2.7±1.9% to 4.3±1.9% ( P =0.022). Hyperviscosity, high Hb, or both, actively contribute to acutely reversible impairments in FMD in EE, suggesting that this plays a pathogenic role in the increased cardiovascular risk.
Take a look at these plots from the study:
Refresher on FMD:
Now couple this information with my previous post on the same Hct values giving very different blood viscosity:
Remember this plot:
From the paper’s discussion:
Blood viscosity elicits opposing resistive and shear stress-associated vasodilatory effects on hemodynamics.51,52 Modest increases in blood viscosity have been shown to reduce blood pressure via increased shear stress-associated NO formation but increasing viscosity >50% increased blood pressure.52 Moderate polycythemia may be associated with greater FMD in hypoxemic patients.53 However, the relationship between blood viscosity and Hb becomes steeper in Andeans with EE (Figure 1). Although the mechanisms that determine this relationship remain to be established (see below), endothelial dysfunction in instances of high levels of blood viscosity and Hb may render individuals especially susceptible to increased cardiovascular risk as both whole blood viscosity54,55 and reduced FMD56,57 predict cardiovascular risk and events.
Enlarged brachial artery diameters have previously been reported in participants with EE,10 which appears to be a phenotypic characteristic of this maladaptive response to chronic hypoxemia. The large diameter may be the result of structural adaptations in response to high blood viscosity-associated shear stress, the so-called shear stress normalization hypothesis.58,59 Additionally, there may be a role for chronic hypoxemia in maintaining the conduit artery in a vasodilated state, supported by the observation that oxygen supplementation decreases brachial artery diameter in patients with CMS.10 Thus, enlarged conduit artery diameter is a fundamental component of EE pathophysiology. In non-EE populations, an inverse relationship between baseline diameter and FMD has been observed.60 This has been interpreted to suggest that the same endothelial function is reflected by a progressively smaller percent and absolute FMD response as baseline artery dimensions increase.60 However, FMD increased with hemodilution while baseline artery diameter did not change, providing support that the larger baseline diameters per se do not explain the impaired FMD in EE.
We have identified a role for high Hb and blood viscosity in contributing to the reduced FMD in Andeans with EE. However, the mechanisms responsible for the low FMD in Andeans with EE are likely multifaceted and cannot be completely elucidated from the present study. For instance, increased systemic free radical formation has been reported in Andeans with EE compared to Andeans without,8,12 and this likely contributes to the lower FMD by chronically inactivating NO (oxidative-nitrosative stress).8,50 Additionally, cell-free Hb is a 1000-fold more potent NO scavenger[61–64](https://www.ahajournals.org/doi/full/10.1161/HYPERTENSIONAHA.119.12780#R61 R62 R63 R64) than red blood cell Hb and can impair endothelium-dependent vasodilation.61,65 Polycythemic patients at sea level have elevated levels of cell-free Hb compared to healthy control participants, and polycythemic patients with hypertension have higher cell-free Hb compared to normotensive polycythemic patients.66 Thus, cell-free Hb may play a role in the NO scavenging and subsequent reduced FMD and increased cardiovascular risk in Andeans with EE.1 Further, measures of erythropoietin to soluble erythropoietin receptor (an erythropoietin antagonist) ratio may have provided additional mechanistic insight, as this ratio is increased in CMS67,68 and erythropoietin has been shown to impair endothelial function in humans.69 Therefore, future investigations should investigate markers of oxidative stress, NO bioavailability (in both plasma and red blood cell), cell-free Hb, and levels of erythropoietin to better dissect the mechanisms linking EE with reduced FMD and related adverse vascular outcomes.
So if you’ve got autoimmune issues, high cRP, elevated plasma viscosity, probably a good idea not to run your Hct up too high! Also, there’s no magic cutoff at a Hb of 21 g/dL. The plot of FMD vs blood viscosity is continuous and shows why cautious providers don’t want to run Hct above 50-51%.