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350 Iyngkaran et al. | Journal of Clinical and Translational Research 2023; 9(5): 347-356
regulations are well described [14]. The NO-cGMP pathway gains, two points are worth reflecting on; the epidemiology of
requires a host of factors including a substrate (L-arginine) and diseases is transitioning and the risk factors, main etiologies, and
cosubstrates (oxygen and NADPH), enzyme cofactors [Flavin demographics, among others, are evolving [5,34]. Today, diastolic
adenine dinucleotide (FAD), flavin mononucleotide (FMN), and HF or HF with preserved ejection fraction (HFpEF) accounts
(6R-)5,6,7,8-tetrahydro-l-biopterin (BH4)], intermediary proteins for 50% of all CHF cases and is more prevalent in older adults,
(e.g., calmodulin [intermediary calcium-binding messenger particularly females [1]. Second, miscellaneous unanticipated
protein]), and trace minerals (e.g., zinc). In CHF, the NO pathway findings can be observed when post-trial real-world data starts
is under stress and a redox state emerges. Elevated production of emerging, as discussed in the first segment [35]. These are among
superoxide radicals and other oxidant species (ROS) with a decline the strongest arguments to learn and reflect on observations.
in elimination is defined as oxidative stress. The mitochondria are 3.1. The process of reflecting on achievements
the main source of ROS that inflicts cellular and DNA damage and
reduced NO effects [16,21-24]. With HF, endothelial dysfunction An article published a decade ago by Atkinson highlighted that
and accumulation of ROS diminish the ability of mitochondria over the span of 40 years, statins constituted 25% of the top 15
to perform their functions. Oxidative stress is also a common best-selling drugs at the time, and 50% of these drugs entered
denominator between HF, endothelial dysfunction, and skeletal the market more than 30 years earlier. The author highlighted
muscle dysfunction [25-27]. We discuss this in the next section. possible reasons as duration of drug development from synthesis
to marketing, and economics which favor copying over
2.2. Skeletal muscle and HF innovation. From these observations, Atkinson quoted “Albeit,
HF induces skeletal muscle myopathy with inflammation, looking at these figures, a pessimist would be tempted to say that
oxidative atrophy, declining strength, acute injury, and impaired cardiovascular pharmacologists have shown a certain lack of
regeneration. This myopathy is unique to HF and creates a loop imagination – an optimist would say that there is a large number
that further declines exercise tolerance [28-31]. These factors of potential targets out there just waiting to be discovered and
are summarised in Figure 2. Essentially, the skeletal muscle is developed” [36]. Whether one or the other perspective is true,
at the forefront of a cycle where its integrity and function are here, the pessimistic argument is propagated. For the individual,
altered by reduced perfusion. In return, the reduced function diseases prosper when the efficiency of communication between
impairs actions that help the movement of blood in the venous any intrinsic feedback loop or extrinsic management option is
system such as those supported by muscle contraction, and unhealthy. These communication issues are factors in common
one-way valves. With structural changes, cellular atrophy can for success at the bench (laboratory) and the bedside (health
lead to apoptosis or permanent dysfunction. There are critical services). With GDMT, the achievement of pharmacotherapy
pathways here that trigger these processes. Thus, the NO pathway addresses but one component of well-being and is thus prescribed
and skeletal muscles have important links. Impaired blood flow in conjunction with multidisciplinary care and a holistic appraisal
of a variety of intrinsic factors. This cannot be better emphasised
also alters skeletal muscle fatiguability. Endothelial dysfunction by the lower attainment of outcomes with proven drugs
and its contributor oxidative stress are directly associated with prescribed at the population level compared to the same drug
mitochondrial dysfunction, microvascular dysfunction, exercise when used in controlled trials [6]. Thus, an introspection on the
intolerance, and insulin resistance in HF [32,33]. epidemiology of the original problem is a vital part of reflecting
There are many contributors to exercise intolerance in CHF, and on achievements.
the direct symptomatic or perceived fatigue attributed to skeletal
muscle fatiguability is not clear, although it likely plays a major 3.2. Epidemiology: Linking the past to reshaping the future
role. Studies have shown that systolic dysfunction in isolation
does not contribute to exercise intolerance or fatigue. A cascade of The last 5 decades have seen stellar advancements in CHF
events with high sympathetic output and low cardiac output leads research (Figure 3). The Framingham study, a pioneering
population study, was the impetus for an increased understanding
to reduced perfusion, changes in skeletal muscle metabolism and of CHF epidemiology . From this point, a revolution in
2
atrophy, pro-inflammatory cytokines, reduced NO availability, cardiovascular medicine took form. Scientific understanding
altered oxidation, and glycolysis [28]. Importantly, with the advent and technological advancements took many shapes. First, basic
of rehabilitation, both NO and muscle changes can be addressed sciences led to improvements in diagnostics including cardiac
with the right program. catheterisation which helped improve clinical pathophysiology.

3. Perspective on Observations and Traditional Clinical This interlink in advancements opened up more areas that delivered
Laboratory Links pharmaceuticals and extended to device-based technologies.
Second, the evidence-based movement (EBM) standardised this
Filling in the clinicopathophysiology gaps was instrumental in process and led to clinical guidelines. Third, from guidelines,
the development of the main CHF therapies. Guidelines weaved post-trial standards were factored in, for example, process of care
these therapeutic pillars with ancillary care to shape comprehensive programs like OPTIMIZE-HF followed by Fonarow et al. [8].
management programs, which work for many patients with We are currently at the point where GDMTs are significant, yet
improved outcomes and quality of life. Before reflecting on these outcomes lag in some areas.
DOI: http://dx.doi.org/10.18053/jctres.09.202305.23-00010