4. What implications do the present findings have for
preclinical practice in
HF?
In the past three decades, there have been few areas of medicine where
significant progress has been made in the treatment of HF. However,
progress was consistent only in chronic HF with reduced ejection
fraction. In acute decompensated HF and HF with preserved ejection
fraction, no treatment has been proven to improve survival. At present,
several kinds of drugs on the market, such as ACE inhibitors,
angiotensin II receptor blockers type I (ARB), beta blockers (BBS),
aldosterone receptor blockers (ALRB), statins, as well as anticoagulant
and anticoagulant therapy, have proved to be effective in achieving hard
targets; however, the mortality reduction of most drugs is less than
30% and the residual cardiovascular risk is still high. Therefore,
efforts to find new methods in the field of HF treatment have not
stopped, and HF treatment drugs based on new mechanisms are constantly
being discovered (Table 3 ). One of the most remarkable is the
unexpected harvest of SGLT2 inhibitors in the treatment of HF. In May
2020, farxiga (empagliflozin) successfully passed the fast track
qualification (FTD) and became the first SGLT2 inhibitor approved for
the treatment of HF. In preclinical studies, the rate of cardiac
remodeling in the non-diabetic pig model group with left anterior artery
ischemia treated by empagliflozin decreased (Santos-Gallego et al.,
2019). Although the precise mechanism of SGLT2 in treating HF is not
clear, it put forward new demands for cardiovascular disease research,
that is, to study on more complex disease models.
4.1 Study on animal model of HF induced by multiple
stimulus
In view of the outstanding contribution of SGLT2 inhibitors in the
treatment of heart failure, it suggests that these diseases have a
common pathogenesis, However, many pharmaceutical companies and
scientists currently focus on developing a single ”mechanism” therapy.
As outlined in the previous section, in the past century, many research
institutions and investigators worldwide have developed a large number
of animal models and assessment methods, which cover different aspect
that could resemble clinical characteristics HF in human. Therefore, the
key to successful preclinical development in the future lies not in
developing more HF models, but in modifying existing animal models to
better imitate complex clinical situations. As initiating triggers for
HF pathologies are highly diverse and the disease processes typically
complex, each animal model of HF produced by single stimulus has obvious
defects, so the combination strategy produced by multiple stimuli may be
a better model to mimic disease conditions in human. There are already
many ongoing efforts in this regard. Given the limitation of the
reversible nature of rapid pacing model alone, Shen et al. combined
rapid ventricular pacing with sequential coronary artery occlusion and
banding aorta respectively, developed two multi-stimulus induced animal
models (Y.-T. Shen et al., 2017). From which it was observed that
banding aorta alone (which would cause left ventricular hypertrophy) did
not reduce baseline cardiac function. But when myocardial ischemia or
left ventricular hypertrophy is combined with pacing, decreased left
ventricular dP/dt and increased left ventricular end diastolic pressure
was observed. The combination of two different methods provides a better
model to mimic the clinical phenotype of human heart failure, which
would provide a unique opportunity for elucidation of cardiovascular
disease mechanisms and also the evaluation of novel interventions. In
some other studies, stimulus combined with transgenic animal models has
become a common strategy for studying pathology and pharmacology of HF.
4.2 Highlighting the application of biomarker detection in
animal model
study
The frequency of positive Phase III clinical trials with investigational
HF drugs has decreased over the past 20 years, while the rate of
positive Phase II clinical trials with surrogate end points remains
high. Although there are many compelling cases of biological
plausibility, past experience strongly suggests that there is no
reliable surrogate end point for the Phase III HF trial outcome (Greene
et al., 2018). It has been found that the development of novel
biomarkers may be more effective than the use of surrogate end points,
and the evaluation of biomarkers is more repeatable and results more
reliable in animal models than mimicking complex cardiovascular disease.
Biomarkers can help detect the presence of heart failure, determine its
severity, assess the risk of future events, and guide treatment, when in
combination with clinical and physical assessments can provide greater
diagnostic accuracy than physical assessments alone (Chow et al., 2017).
Since the establishment of natriuretic peptide as a diagnostic criterion
for heart failure in 2000, the evaluation of biomarkers has been
included in a large number of preclinical studies (Januzzi & Felker,
2013). However, defining a “rule-in” cutoffs for HF is complicated
because multiple factors influence natriuretic peptide levels for heart
failure is complex because of a variety of factors that affect
natriuretic peptide levels. Thus, other potential strategy explored a
multimarker approach for predicting new-onset HF. In the subset of
patients with high baseline risk determined by clinical parameters, the
best models for predicting new onset HF include N-terminal pro-B-type
natriuretic peptide (NT-proBNP), troponin T (TnT), and urinary albumin
excretion(Chow et al., 2017). Introducing these indicators of biomarkers
into animal model research not only can be used to distinguish the
subtypes of HF of animal models with different clinical features, but
also can help evaluate the pharmacological efficacy studies of drugs by
combining the results from physiological and echocardiography
parameters. Indeed, biomarkers have been used in association with many
preclinical studies that have been completed or are ongoing
(Table 2 ). Recently, a novel study demonstrated an increase in
NT-proBNP levels in the dog I/R model, in contrast, LV mechanical
unloading by the total support of transvascular LV assist device Impella
could reduce LV end-diastolic pressure, increase LV end-systolic
elastance and decrease NT-proBNP level, thereby preventing subsequent HF
(Saku et al., 2018).