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involvement of different mechanisms through the expansion of organ damage
(excessive proinflammatory factors, endothelin, adiponectin)?
(c) The same disease, with the same mechanisms, but the arbitrary cutoffs used for
definition are imperfect (old age, morbid obesity)?
The polemics start from the fact that RH is an entity identified retrospectively,
following a dead-end reached in the treatment of firstly presumed essential hyper-
tension, and based on two fundamental suppositions: (1) we presume the hyperten-
sion is essential, and (2) we must exclude secondary hypertension, the causes for
noncompliance to treatment, and pseudo-resistant hypertension. Hence, if we are to
be completely honest, in approaching and characterizing a true RH, we do not know
with absolute certitude if it is secondary hypertension, if there are certain underly-
ing causes for a pseudo-resistance, or if it is, indeed, a true RH.
The treatment entails rules applicable to a majority of patients, who would
respond out of “common sense” to the current treatment schemes. Thus, the criteria
for “resistance” to treatment also represent the criteria in the diagnosis of
RH. Concurrently, this provides us with the possibility (at least in theory) that the
definition of RH could (and would) be modified with the identification of a new
class of drugs or the adjustment of the therapeutic strategy.
Within this context, we believe that, despite the ESC classification, the reversible
forms of RH triggered by various extrinsic factors such as excessive alcohol con-
sumption, high sodium intake, and vasopressor drugs should be excluded from the
definition of true resistant hypertension, as removal of the external causes leads to
the reversibility of the condition.
Furthermore, we can place at the border between essential and secondary hyper-
tension the particular form of RH associated with various comorbidities/cardiovas-
cular risk factors (diabetes mellitus, obesity, chronic kidney disease, sleep apnea).
We can argue that the interaction between the induced neuro-metabolic and vascular
alterations due to comorbidities and the specific mechanisms involved in essential
hypertension has an augmenting effect, which generates a form of RH with partial
reversibility and treatment resistance. Conversely, since the evolution of RH cannot
be predicted through the strict management of these conditions, they fall within the
category of borderline true RH which we will discuss further in this chapter.
As we begin our exploration of the physiopathological mechanism underlying
this ambiguous and dynamic condition, there still remain several uncharted territo-
ries. Two issues that still remain under debate are as follows: (1) Is there a genetic
or molecular determinism to be investigated in resistant hypertension? (2) To what
extent do common cardiovascular risk factors bear an influence upon the response
of any form of essential, borderline, or resistant hypertension to treatment?
We believe that searching and/or identifying completely the core mechanism of
this entity would allow (1) the identification of novel therapeutic pathways and (2)
the upgrade of the inclusion criteria of clinical trials (e.g., renal denervation), which
would lead to more veridical and useful results (free from intervention of subjective
factors such as adherence to treatment).
A. Burlacu and A. Covic