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348 Iyngkaran et al. | Journal of Clinical and Translational Research 2023; 9(5): 347-356
There are examples of extending innovation from established HFrEF [10]. The pioneering hydralazine (arterial dilator)-
therapies, from clinical intuition and exceptional bench to bedside nitrate (venodilator) Vasodilator HF Trial (V-HeFT trial) in 1986
translational research. Two such advances in the last decade are demonstrated improved survival in HFrEF. In 2004, the African-
the angiotensin receptor-neprilysin inhibitors (ARNIs) as an American HF Trial (A-HeFT trial) improved on mortality
extension of the renin-angiotensin system and sodium-glucose reduction of V-HEFT from 34% to 43%. The pathophysiology
cotransporter-2 (SGLT-2) inhibitors and extension of incidental targeted was primarily reducing intracardiac filling pressures and
observations in diabetes studies [1,2]. These examples highlight altering cardiovascular negative remodeling, and secondarily
the importance of post-trial observations. increased nitric oxide (NO) availability both as a donor and with
Noting it can be decades between such important discoveries, antioxidant properties [11]. In between these studies in 1997,
clinicians will undoubtedly question who, how, and when will the angiotensin-converting enzyme inhibitor (ACE-i) trials
newer discoveries come along. Feasible contributions clinicians established this as the first pillar in therapy. Here, enalapril
can make in their daily routines are interrogative bedside superseded the vasodilator combination in mortality. However,
observations and where relevant, direct a bench connection. among the 215 black versus the 574 white patients, there was
For this discussion, we acknowledge that the understanding of no difference in either arm. A speculation was the efficacy of
cardiovascular disease through vascular endothelium, smooth, ACE-I in reducing blood pressure in Black patients [12]. In the
and skeletal muscle pharmacology reminisces great achievements real world, observations from two studies first showed that in
in medicine and is an opportunity to ignite debate on gaps and Black patients above 65 years, 18% had an estimated glomerular
challenges. In this short communication, we first highlight a basic filtration rate (eGFR) of <30 mL/min/1.73 m and the actual use
2
understanding of key CHF processes in the endothelium and of proven vasodilators in those who have contraindications to a
skeletal muscle; in the second part, we explore key challenges in CHF pillar or who qualify outright was low [10,13-15].
epidemiology and drug discovery; and finally, we discuss ideas To advance these arguments, we draw on a simple perspective
that may not be traditional; however, the direction of which could of biological systems, as they are seen as being composed of
be important to find research questions to expand on established compartments. External compartments are outside the system.
therapies. Internal compartments are separated by function, synergy,
Heart failure (HF) in this review is focused on HF with reduced distance, or other barriers. Importantly, pathways beyond routine
ejection fraction (HFrEF). Other forms of HF have different facilitation are activated to overcome barriers. Through mediators
pathophysiology and are not discussed. that act outside a cell or downstream through a cellular receptor
counter regulatory mechanism creates the milieu and equilibrium.
2. Gaps Beyond the External Validity of Delivering Several important pathways and downstream links in CHF that
Guideline-directed Therapies have not seen revolutionary prognostic treatments, despite playing
There are four pillars of CHF pharmacotherapies published in key roles in its pathophysiology are the endothelium (excluding
established guidelines (Figure 1) [1,2]. These therapies that were vasodilator studies) and skeletal muscle.

developed over decades are examples of successful clinically 2.1. Endothelium in HF
translated bench-to-bedside discoveries. CHF affects all organs
and utilises many counter regulatory pathways. Some pathways In CHF patients, endothelium-dependent vasodilatation is
play a greater role in CHF pathophysiology. Other pathways blunted due to abnormal NO production and actions [16-18]. Many
are also important and holistically contribute to chronic disease CHF treatments aim to restore this balance. Endothelium, the
propagation. Thus, comprehensive care requires a multimodality largest organ in the body, originates from embryonic mesoderm.
approach including allied health participation. All established It is a single layer of cells that lines the entire circulatory system,
guidelines detail a framework for comprehensive care. Therapeutic including the heart, blood vessels and lymphatics, and the smallest
response creates a new equilibrium as these pathways navigate capillaries of all other organs in the body. Physiologically,
from the disease state to the new milieu and vice versa. As there vasodilator and constrictor factors, predominately NO and
are differences in individual outcomes, if we assume GDMTs have endothelin, regulate structure, function, and dynamism [18]. The
been delivered, according to protocol, this leaves us with several endothelium exerts multiple biological effects through endocrine
questions: Do differences in response warrant a search for new and paracrine signaling pathways. It also responds to various stimuli
therapies such as a fifth or sixth pillar; or alternatively exploring and has broader actions such as platelet aggregation, leukocyte
the question through renewed bedside observations may highlight activation, smooth muscle cell proliferation, neurotransmission,
pathophysiological clues on how some patients are responding? cardiac contractility, anti-tumor, and pathogen, and inflammatory
This post-trial introspective approach allows clinicians to go effects, thus maintaining vascular general homeostatic control
beyond the grouped outcome data of a trial and individualise an (Figure 2) [19]. Endothelial dysfunction occurs from an imbalance
outcome for the patient. Thus, it can then generate new hypotheses in vasoregulatory actions, leading to a reduction in flow-mediated
to take back to the bench. dilatation or vasoconstriction in response to agonists, such as
There are some examples of this. The A-HEFT study acetylcholine. Impaired synthesis and inactivation of the relevant
had important implications for treating Black patients with bioactive compounds are then critical to disease development [20].
DOI: http://dx.doi.org/10.18053/jctres.09.202305.23-00010