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352 Iyngkaran et al. | Journal of Clinical and Translational Research 2023; 9(5): 347-356
with wide benefits. This suggests that translational solutions that biochemically as low renin and aldosterone and overactivity of
encompass all comers are difficult and new approaches may be ENaC [44,45]. Thus, in isolated CHF, as population heterogeneity
needed. Beyond current GDMT, a holistic and invasive (above) increases with chronicity and greater complexity, more factors are
approach has failed to improve outcomes, in patients receiving encountered outside the trial inclusion and this requires ongoing
optimal GDMT. Thus, a holistic trial approach, at some point observations to filter potentially significant findings.
needs to consider individual factors such as disease chronology
and severity itself, demography (age, sex, and ethnicity), and a 4.2. Chronic illnesses and evidence-based medicine
host of unconventional factors [37]. As there are physiological Complex and multimorbid illnesses are confounders to
differences to factor in, this could be important [38-41]. finding proof of causation. Population heterogeneity that
4. Defining the Translational Issue of Complex Care contributes to this complexity includes a higher prevalence of
traditional and nontraditional risk factors, gender, age, ethnicity,
In considering the issues of translating findings from RCTs sociodemographics, and multiple chronic comorbid illnesses.
and finding solutions for complex and chronic care, this can only These comorbid conditions and demographics can influence the
be answered when the perspective of the question or problem is baseline when comparing a treatment and placebo. When we
encountered and defined. Cause and effect are proven in trials; add in the cost of RCTs and the feasibility of bench-to-bedside
however, unforeseen gaps are identified in clinical translation. translation in cost and time, the ability to find meaningful
Should these gaps relate to a new disease pathophysiology, new answers for today’s chronic ailments such as CHF becomes more
pillars of treatment can be explored as highlighted with NO challenging, especially post-trial findings. The existing tools are
and skeletal muscle. However, it is gradually being recognised there to allow hypothesis generation, broad observations and
that complex care may determine responses beyond the means to inform cost-effectiveness when evidence is established.
pathophysiological pathways controlled for in trial settings. This What is different, however, is the level at which we are able to
idea could shape post-trial CHF management, and this is discussed. advance these topics and methodologies we utilise.
Thus, the question is how do we better employ the technology
4.1. Anecdotal evidence for observational paradigms in complex care that understands pathophysiological mechanisms, for predicting

Under-representation of demography, ethnicity, gender, and decompensation, preventing readmissions, and reducing costs?
complexity of cases are recognised flaws for translational goals What are the population level gaps for CHF? Patients who are
from RCT findings [35,36]. While they are gold-standard for good self-managers are invariably better at relaying information
proving causation, the actual issue is not the result but its application to their teams. Good self-management requires a degree of
when administered to untested heterogeneity, which is the norm cognitive behavioral changes. However, there are confounders,
in a real-world clinical setting. Registries and anecdotal post hoc treatments will improve symptoms, and comorbidities such as
data are traditional sources for identifying these issues [7]. As an renal impairment, coronary artery disease, diabetes, and atrial
example, among indigenous peoples with chronic diseases in North fibrillation can aggravate HF [7,9]. Symptoms can also be
America and Australasia, this group represented 5.6% of the total confounded by these conditions and biomarkers like N-Terminal
population in 172 of 1000 studies reviewed . In cardiovascular Brain Natriuretic Peptides (NT pro-BNP) can be elevated. The
42
trials, from 2015 to 2019, African Americans younger than chronology of chronic HF can cause symptoms and biomarker
65 years only represented 3% of clinical trial participants [39,42]. levels to change at varying stages [7,9]. Thus, chronic illnesses
Among indigenous Australians, established genetic variation have individual fingerprints, while acute illnesses can respond
with rheumatic heart disease was identified at a locus related to to management strategies along a more singular, universal, and
immunity responses (HLA_DQA1-DQB1) [4] and with kidney GDMT line. This argument is probably the most relevant, as the

diseases an uncharacteristically high susceptibility to renal stress, health system devises models to address chronic disease cost,
renal failure associated with lower nephron numbers with ACE outcome, or cost-effectiveness. As there is no fixed baseline of
D alleles [39]. Across the board, there is established evidence health for patients at first presentation, nor are there predictable
of differences in risk factors and diseases in groups of peoples trajectories, are individual fingerprints on health needed, and is
(e.g., race and gender), from single nucleotide polymorphisms to there a molecular basis for this, and for post-trial scenarios such
multiple genetic abnormalities, to systems such as cytochomone as predicting early deteriorations?
P450 and receptors such as the adrenergic systems [39]. 4.3. Entropy
Specific examples of these paradigms have even come from
trials and follow-through with observations in the cohort subgroups Could entropy in a medical sense have relevance? If so, it could
and registry of real-world recipients of the medication. The most help start discussions on novel post-trial observational paradigms,
notable subgroup (African Americans) included in A-HEFT [43] which include factoring common denominators in complex cases,
and the ALLHAT [36] study, shaped an important understanding or responses in patients with multiple comorbid conditions who
of the pathophysiology of hypertension in this population. demonstrate unexplained treatment responses. A simple definition
Hypertension was observed to be more severe and resistant, from of entropy is the measure of the amount of energy in a system
genetic predisposition to retaining salt and water, manifesting that cannot contribute to work. Importantly, for our argument,
DOI: http://dx.doi.org/10.18053/jctres.09.202305.23-00010