Drugs (2016) 76:187201

DOI 10.1007/s40265-015-0498-3

LEADING ARTICLE

New Targets in the Drug Treatment of Heart Failure

James A. Iwaz1,2 Elizabeth Lee2 Hermineh Aramin2 Danilo Romero2
Navaid Iqbal2 Matt Kawahara2 Fatima Khusro2 Brian Knight2
Minal V. Patel2 Sumita Sharma2 Alan S. Maisel1,2

Published online: 11 December 2015

Springer International Publishing Switzerland 2015

Abstract Heart failure is a complex syndrome that has

been a major contributor to readmissions into hospitals in the
USA. Currently, a large number of medications are being
used to treat the symptoms of the diseasedigoxin, diuretics, renin-angiotensin-aldosterone system inhibitors, bblockers, and vasodilators. There is no doubt that the given
pharmaceutical therapy has been effective in lowering hospital readmission rates and prolonging life in individual
chronic heart failure patients. Despite this, admission rates
following heart failure hospitalization remain high, resulting
in a substantial financial strain on healthcare institutions.
Clearly, there is much room for improvement in heart failure
therapy and management in reducing readmission rates. In
this review, we address the unmet needs in the current drug
treatment of chronic heart failure and describe novel drug
targets that are currently under investigation.

Key Points
Novel approaches to heart failure therapy should
target intracellular processes.
Biomarker-guided therapy with novel drug
treatments may reduce readmissions in heart failure
patients.

& Alan S. Maisel

amaisel@ucsd.edu
1

University of California, San Diego Medical Center,

San Diego, CA, USA

Veterans Affairs Medical Center, VA San Diego Healthcare

System, 3350 La Jolla Village Drive, San Diego, CA 92161,
USA

1 Introduction
Heart failure (HF) is a leading cause of morbidity and mortality worldwide. It is a chronic and complex syndrome and
represents the end stage of a variety of different cardiac
conditions, such as ischemic heart disease, hypertension, or
non-ischemic cardiomyopathy. HF occurs when the ability
of the ventricle to either fill with or eject blood is impaired,
which can lead to congestion and decreased cardiac output.
HF is commonly subdivided based on ejection fraction into
HF with reduced ejection fraction (HFrEF) and preserved
ejection fraction (HFpEF), each of which roughly account
for half of the cases of HF. Both HFrEF and HFpEF can
present with similar symptoms; however, they have different
pathophysiologic mechanisms. In HFrEF, reduced left ventricular (LV) systolic function leads to a decreased EF and
cardiac output, resulting in decreased systemic perfusion.
HFpEF results in abnormal diastolic dysfunction and
impaired relaxation of the left ventricle, which leads to
impaired filling of the left ventricle. Decreased filling of the
left ventricle during diastole can lead to decreased cardiac
output, despite a normal EF. Patients with HFpEF rely
heavily on diastolic filling time and are exquisitely sensitive
to heart rate, which is why tachyarrhythmias can cause rapid
decompensations in these patients. Both HFrEF and HFpEF
result in increased congestion, leading to increased pulmonary and right-sided pressures. This leads to pulmonary
edema and elevated venous pressures, explaining some of the
common signs and symptoms of HF such as shortness of
breath and lower extremity edema. Both HFrEF and HFpEF
have many underlying pathophysiologic mechanisms,
including increased neurohormonal and sympathetic activity. These mechanisms contribute to LV modeling and are a
major driving mechanism behind the chronicity of HF.

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HF is an end-stage disease that can be due to a variety of

etiologies, such as coronary artery disease, hypertension, or
tachyarrhythmias. Despite that HF can be due to a variety
of cardiac conditions, HF has a common pathophysiologic
mechanism such as increased neurohormonal activation.
Neurohormonal mechanisms such as the sympathetic nervous system (SNS) and renin-angiotensin-aldosterone system (RAAS) help to maintain cardiac output in normal
physiologic states. In HF, there is an increased amount of
circulating catecholamines (CA) throughout the body,
leading to increased neurohormonal activity. Increased
activity of SNS and RAAS in HF results in LV dysfunction
and remodeling and is associated with worse prognosis [1].
Beta-blockers (b-blockers), angiotensin-converting enzyme
(ACE) inhibitors, angiotensin II receptor blockers (ARBs)
and mineralocorticoid receptor antagonists (MRAs) are
used to treat HF for this reason [2].
Acute decompensated heart failure (ADHF), which is an
acute exacerbation of chronic HF, accounts for 80 % of the
hospitalizations that are due to HF [37]. Even with
advances in treatment, mortality and morbidity remain
high. The aggregation of the costs from frequent rehospitalizations due to HF puts a large financial strain on
healthcare institutions [36, 8]. The aim of this article is to
discuss some of the intracellular pathways in the pathophysiology of HF and novel drug treatments of HF. A literature search was performed on PubMed and
clinicaltrials.gov.

2 Unmet Needs in the Current Drug Treatment

of Heart Failure (HF)
Since HF can be due to a variety of underlying conditions,
the initial treatment is focused on treating the underlying
cause. Standard HF pharmacotherapy usually consists of
ACE inhibitors or ARBs, MRAs, and b-blockers. They are
effective in improving symptoms and hemodynamics and
reducing hospitalizations, and have been shown to improve
mortality [3, 4, 9, 10].
A majority of the current research has found improved
mortality with use of b-blockers, ACE inhibitors, and
aldosterone antagonists in patients with HFrEF. Despite the
common symptomatology between HFrEF and HFpEF,
research on HFpEF and ACE inhibitor or ARB use has had
mixed results [1116].
Digoxin and diuretics are also commonly used to treat
symptoms in HF, but have not been shown to improve
mortality [17]. It is worthy to note that these medications
carry the risk of side effects. For example, digoxin has
many side effects, including cardiac arrhythmias, gastrointestinal symptoms, and neurological complaints.
Patients who are elderly or have chronic kidney disease

J. A. Iwaz et al.

have an increased risk of these side effects. Concomitant

use of clarithromycin, dronedarone, erythromycin, amiodarone, itraconazole, cyclosporine, propafenone, verapamil, or quinidine can increase serum digoxin
concentrations and increase the likelihood of digoxin toxicity. Diuretics can cause electrolyte and fluid depletion,
which if left unchecked can lead to serious cardiac
arrhythmias. ACE inhibitors run the risk of hyperkalemia,
induced cough in up to 20 % of patients, and angioedema.
ARBs can lead to hypotension, renal dysfunction, and
hyperkalemia, especially when combined with ACE inhibitors. b-Blocker side effects can include fluid retention,
fatigue, worsening HF, bradycardia, heart block, and
hypotension. Aldosterone receptor antagonists may cause
hyperkalemia due to inhibition of potassium secretion.
Finally, hydralazine and isosorbide dinitrate have higher
incidence of headache, dizziness, and gastrointestinal
complaints with frequent administration [18].
Currently, HF pharmacotherapy focuses on decreasing
or reversing cardiac remodeling and myocardial dysfunction. A novel approach to treatment would be to target key
intracellular signaling pathways, which may lead to further
improvement in mortality and readmission, with decreased
side effects. Drugs that focus on the pathophysiologic
mechanisms of HF may lead to improved symptoms,
decreased mortality, and decreased readmission rates.
There are several targets and drugs under investigation that
could complement the current standard of care. In addition,
current research on medications in HF show a mortality
benefit mainly in HFrEF as discussed above. There is a
need for more targeted pharmacotherapy for HFpEF in the
hopes of improving mortality.

3 Neurohormonal Targets
3.1 Galectin-3
Galectin-3 (gal-3) is a 29- to 35-kDa protein of the lectin
family that is involved in several biological processes
throughout the body, including the immune response,
inflammation, cell growth, and cell differentiation [19, 20].
It also plays a key role in the pathophysiology of HF.
Multiple studies have shown that gal-3 levels are associated with prognosis in HF patients, which also makes it a
potentially valuable therapeutic target [2125]. When the
myocardial tissue of the heart begins to fail, many genes,
including those for gal-3, become overexpressed as part of
an inflammatory response [26]. Gal-3 induces fibroblast
proliferation and activation [19]. Once activated, the
fibroblasts differentiate into myofibroblasts, which produce
and secrete collagen into the interstitium, resulting in cardiac fibrosis and remodeling. Thus, inhibiting gal-3 may

New Targets in Heart Failure

decrease the cardiac inflammation in the early stages of HF

and halt the progression of gal-3-mediated cardiac
remodeling in chronic HF.
The utility of gal-3 inhibition in treating chronic HF has
thus far been confirmed in animal models [20, 25, 27, 28].
In the first of such studies, gal-3-mediated cardiac
remodeling was decreased and reversed by treatment with
Ac-SDKP (N-acetyl-seryl-aspartyl-lysyl-proline), a naturally occurring peptide with anti-inflammatory and antifibrotic properties [29]. In this study, rats developed cardiac hypertrophy and fibrosis after intrapericardial infusion
of gal-3; however, when Ac-SDKP was administered with
gal-3, hypertrophy and fibrosis were not seen [20]. Further
support comes from a landmark study involving the gal-3
inhibitor N-acetyllactosamine, which has a high affinity for
the gal-3 carbohydrate recognition domain. In another
animal model, mice had transverse aortic constriction
(TAC) or angiotensin II infusions resulting in cardiac
remodeling. Researchers found that N-acetyllactosamine
infusion attenuated cardiac remodeling. N-acetyllactosamine also significantly decreased the amount of cardiac
fibrosis in HF-prone REN2 rats and ceased the progression
of adverse remodeling. The study also showed that gal-3
knockout mice were protected from LV dysfunction caused
by TAC or angiotensin II infusion, providing further evidence for the role of gal-3 in the pathophysiology of
chronic HF [25]. Another gal-3 inhibitor is modified citrus
pectin, which also acts by binding to the carbohydrate
recognition domain of gal-3. In a recent study, rats treated
with aldosterone developed hypertension and vascular
remodeling, while rats given concurrent treatment of
aldosterone and modified citrus pectin did not [28]. In
addition, a similar study investigated gal-3 inhibition in
rats with hyperaldosteronism. Rats were treated with either
spironolactone or modified citrus pectin. The authors found
the increase of gal-3 was associated with cardiac and renal
fibrosis and dysfunction. These adverse remodeling effects
were prevented by treatment with modified citrus pectin
[30]. Another study looked at gal-3 inhibition in rats with
induced myocardial infarction (MI) and systolic dysfunction. They found that rats with MI had increased myocardial levels of gal-3, but rats who were treated with MRAs
had decreased expression of gal-3 [31].
Another study looked at galectin-3 levels in relation to
LV remodeling as well as biomarkers involved with
extracellular matrix turnover in patients admitted with
acute MI. This study found that gal-3 correlated with the
various extracellular matrix biomarkers, but was not correlated with LV remodeling [32]. The HF-ACTION study
looked at treatment effects of MRAs based on gal-3 levels
in humans. This retrospective study did not find a significant relationship between gal-3 levels, MRA use, and
clinical outcomes. Although this study did not find a

189

relationship with clinical outcomes, a prospective, randomized trial could help further examine the use of MRAs
based on gal-3 levels [33]. Results from animal trials
indicate that gal-3 has a role in cardiac remodeling and that
gal-3 inhibition may be a potential therapeutic target in
human populations. Though promising, research in humans
is lacking, and further studies are needed to examine
whether gal-3 inhibition has an effect on clinical outcomes.
3.2 ST2
ST2, a member of the interleukin (IL)-1 receptor family,
has gained considerable recognition in HF research over
the past few years. It was initially discovered in cultured
cardiac myocytes and is a receptor to IL-33. ST2 is
thought to be involved in modifying immunologic processes, specifically mediated by T-helper 2 lymphocytes
[34]. Due to alternative splicing and 30 modification, the
ST2 gene exists in two main forms, a soluble (sST2) and
transmembrane form (ST2L). In the setting of HF, both
sST2 and ST2L become up-regulated due to mechanical
strain on the myocardium [35]. Blood concentrations of
sST2 are increased in various inflammatory disorders and
heart diseases, including HF, making it a useful prognostic marker in both conditions. The cytokine IL-33 has
recently been identified as the ligand for ST2 and may
protect against LV remodeling and myocardial fibrosis
[36, 37]. The interaction between IL-33 and ST2L is
necessary for the protective effect of IL-33; however,
elevated sST2 levels predict severity and poor outcomes
in HF. Patients with HF have elevated sST2 levels.
Because sST2 lacks both the transmembrane and the
intracellular domains of its membrane-bound counterpart
ST2L, sST2 binds to and neutralizes IL-33, which prevents IL-33 from binding to ST2L and decrease LV
remodeling and fibrosis [36, 38].
In acute and chronic HF, sST2 plays a significant role in
predicting HF severity and poor outcome. Several studies
in patients with HF indicate that serial measurement of
sST2 has prognostic value and could have a potential role
in future biomarker-directed therapy.
Anand et al. [39], in the VALSARTAN HF trial, evaluated the relationship of sST2 with outcomes of patients
with HF. sST2 levels were measured at baseline and at 4
months and 12 months. sST2 was significantly associated
with morbidity, mortality, and hospitalization for HF
(p \ 0.0001). Over a period of 12 months, increases in
sST2 were significantly associated with worsening outcomes in HF patients, independent of clinical variables,
baseline sST2 levels, and valsartan treatment.
Gaggin et al. [40] also conducted head-to-head comparisons of serial sST2, growth differentiation factor
(GDF)-15, and highly sensitive troponin T to evaluate the

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role of serial measurements of these biomarkers in patients

with chronic HF. In their post hoc analysis of 151 patients
with chronic HF due to LV systolic dysfunction, all three
novel biomarkers independently predicted total cardiovascular events after adjusting for clinical and biochemical
characteristics, including the N-terminal of the prohormone
brain natriuretic peptide (NT-proBNP), with the best model
including all three biomarkers (p \ 0.001). However, only
sST2 serial measurements independently added to the risk
model (p = 0.009) and predicted reverse myocardial
remodeling and change in LV function (p = 0.01). This
implies that sST2 may be a useful target in patients with
chronic HF.
Lassus et al. [41] recently evaluated the individual and
added value of various novel biomarkers to traditional
clinical variables for risk stratification of 30-day and 1-year
mortality in acute decompensated HF (ADHF). The
biomarkers with the strongest association were sST2
(p \ 0.001) and MR-proADM (p \ 0.001), which also had
the best individual performance for risk stratification at
30 days. For 1-year mortality, sST2 was found to be a
superior marker for risk prediction. The results of this study
suggest that, in patients with ADHF, markers such as sST2
and MR-proADM have the best potential to improve risk
stratification and should be used individually or in combination with other novel biomarkers.
Mueller et al. [42] also commented on the prognostic
potential of ST2 in their study of 137 patients presenting
with ADHF. They demonstrated that higher sST2 levels
were found in patients who died of HF (870 vs. 0.87 ng/ml,
p \ 0.001). They also found that an sST2 plasma concentration of [0.70 ng/ml was predictive of 1-year allcause mortality. This study demonstrated that measuring
sST2 levels at the time patients initially present to the ED
with ADHF might indicate an increased risk of future
adverse events.
These studies demonstrate the potential role of sST2 as a
useful marker of myocardial inflammation and remodeling,
and appear to predict mortality in HF patients. sST2 is a
valuable tool with diagnostic, prognostic, and treatmentguiding properties and can be very useful in clinical
practice. Further research regarding the pathophysiology of
this protein is necessary before using it in a clinical setting.
3.3 Adrenomedullin
Adrenomedullin (ADM) is a 52-amino acid peptide that
was initially isolated from pheochromocytoma extract [43,
44]. Patients with HF have up-regulation of adrenomedullin messenger RNA (mRNA) due to increased volume
overload and action of vasoactive hormones on endothelial
cells [45, 46]. ADM is responsible for decreasing systemic
vascular resistance and promoting natriuresis and diuresis

J. A. Iwaz et al.

[47, 48]. ADM expression can be found throughout the

body, including in cardiovascular, renal, pulmonary, cerebrovascular, gastrointestinal, and endocrine tissues, where
it functions as a circulating hormone as well as a local
autocrine and paracrine effector. Investigators have
demonstrated that increased adrenomedullin levels are
directly proportional to New York Heart Association
(NYHA) functional class. However, due to its rapid
clearance from the blood and short half-life (22 min), ADM
itself is unable to be accurately measured. MR-proADM is
a component of the precursor molecule to ADM that has a
longer half-life than ADM and thus may be used as a
surrogate for ADM [47].
3.3.1 Role of Mid-Regional Pro Adrenomedullin in Acute
and Chronic HF
The multi-center prospective BACH trial evaluated the
prognostic utility of MR-proADM in patients with acute
HF (AHF) presenting to the emergency department with
dyspnea [49]. Results revealed that MR-proADM was
superior to BNP/NT-proBNP in predicting 90-day death or
re-hospitalization due to cardiovascular causes (receiver
operating characteristic area under the curve [ROC-AUC]
for MR-proADM 0.740; BNP 0.682; NT-proBNP 0.724).
Survivors were found to have lower levels of MR-proADM
than did non-survivors (0.84 vs. 1.57 nmol/L, p \ 0.0001).
A follow-up study to the BACH trial concluded that
biomarkers that proved superior to natriuretic peptides in
predicting 14-day mortality were copeptin (ROC-AUC
0.803) and MR-proADM (ROC-AUC 0.742). Furthermore,
combining MR-proADM and copeptin for predicting
14-day mortality resulted in an AUC of 0.818 [48]. Xue
et al. [50] evaluated the prognostic utility of MR-proADM
in stable outpatients with HF. Echocardiogram and MRproADM and BNP levels were obtained in 724 stable outpatients. These patients were followed for up to 6 years for
the primary endpoint of all-cause mortality. Patients with
elevated MR-proADM had significantly increased risk for
mortality in stage A and stage C/D HF, with hazard ratio
(HR) 3.780 (p \ 0.001) and HR 2.744 (p \ 0.001),
respectively.
Von Haehling et al. [51] also evaluated the prognostic
performance of MR-proADM in patients with congestive
HF (CHF) and showed that MR-proADM levels (median
0.64 nmol/L) significantly increased with severity of HF as
determined by NYHA functional class (p \ 0.001). When
compared with NT-proBNP, MR-proADM had higher
sensitivity (83.9 vs. 74.2 %) and AUC (0.81 vs. 0.79).
Finally, MR-proADM levels were predictive of all-cause
mortality independent of EF, creatinine, age, and NYHA
class, and also added to the prognostic potential of NTproBNP.

New Targets in Heart Failure

The high risk of death seen in patients with acute and

chronic HF suggests that it may be difficult to identify
high-risk patients based solely on clinical grounds, and that
measuring MR-proADM could potentially identify patients
in need of more aggressive therapy. Numerous studies
conducted over the last decade have expanded our clinical
knowledge regarding the role of MR-proADM in prognosticating patients with acute and chronic HF. Although
the data suggest that MR-proADM is a robust marker in
predicting mortality in patients with HF, further evidence
determining its superiority to benchmark markers such as
natriuretic peptides is warranted.
3.4 Copeptin
Dyspnea is a common and major symptom of AHF and
results from pulmonary edema and increased salt and water
retention [52]. Arginine vasopressin (AVP) is a wellknown stress hormone and acts as a neuromodulator and
neurotransmitter in HF. The vasopressin system is recognized as one of the most important compensatory systems
in HF. The most important stimuli for AVP release are
changes in plasma osmolality, decreased arterial pressure,
and reduced blood volume.
AVP is a 9-amino acid peptide that has a bridge between
two cysteine amino acids. It is produced primarily by the
hypothalamus and is secreted from the posterior pituitary.
AVP primarily exerts its effect on three different receptors
[52]. V1a receptors are located on vascular smooth muscle
cells, hepatocytes, platelets, and the brain and uterus.
Binding of AVP on these receptors results in arteriolar
vasoconstriction. The V2 receptors are found on the collecting duct of the kidney. Binding of AVP on these
receptors increases water permeability via the aquaporin-2
water channel. The V3 receptors (also known as V1B) are
located on the anterior pituitary gland, pancreas, heart, and
brain. It is involved in adrenocorticotropic hormone
(ACTH) secretion, insulin synthesis, and memory control
[53]. CT-proAVP (copeptin), a C-terminal component of
pre-arginine vasopressin (pre-AVP), directly reflects AVP
concentration and can be used as a surrogate marker of
AVP secretion. CT-proAVP has high plasma stability and
is easier to measure than AVP.
It has been shown that copeptin is a strong predictor of
mortality in patients with acute and chronic HF caused by
MI. Several drugs under investigation have targeted the
receptors acted upon by AVP in the hopes of finding one
that improves outcomes in HF. One trial involved conivaptan, a nonselective V1a/V2-receptor antagonist that was
shown to increase urine output and decrease body weight.
However, it did not improve clinical outcomes of patients
with HF [54]. Tolvaptan and lixivaptan are V2-selective
antagonists that have been used in clinical trials and

191

experimental animal studies. In a clinical trial study,

tolvaptan was administered to patients with signs and
symptoms of CHF and LVEF of \40 %, who were then
compared with a standard therapy group. Although no
adverse effects such as changes of heart rate, blood pressure, or electrolytes were reported, it did not improve the
rate of worsening HF [55]. However, AVP receptor
antagonists have bene shown to play a pivotal role in
treatment of hyponatremia in the setting of CHF [55].
AVP-receptor antagonists prevent cardiac remodeling in
experimental animal models of HF, but have not been
shown to significantly improve morbidity or mortality [52].
The EVEREST trial looked at the use of tolvaptan in
patients with HFrEF and also measured AVP. This study
found that an elevated baseline AVP level was an independent predictor of mortality. They also found that
treatment with tolvaptan resulted in increased AVP levels,
but with no worsening in mortality. However, they did not
find a statistically significant decrease in mortality with use
of tolvaptan in any subgroup [56]. Nevertheless, the AVP
pathway represents a potential target for HF treatment, and
further studies are needed to further characterize the relationship between AVP and use of vaptans.
3.5 Endothelin-1
Endothelin (ET-1), an endothelium-derived peptide, is a
potent vasoconstrictor and pro-inflammatory mediator
produced in response to hypoxia or wall stress, and may
aggravate myocardial ischemia. ET-1 also plays a crucial
role in cardiac remodeling [57]. The ET receptor has two
subtypes: ETA-R and ETB-R. The ETA-R is located predominantly on vascular smooth muscle cells and is
responsible for mediating vasoconstriction and proliferation [57]. The ETB-R is mainly located on endothelial cells
and mediates vasodilation. Plasma ET-1 (pET-1) and its
components, the ETA and ETB receptors, have increased
expression in the coronary arteries after infarction and at
early stages following percutaneous coronary intervention
(PCI). It has been reported that elevated pET-1 levels are
associated with reperfusion injury, microvascular obstruction, and long-term mortality in patients with ST-segment
elevated MI (STEMI) and those who have undergone PCI
[58, 59].
pET-1 levels begin to rise within hours of an STEMI and
remain elevated after PCI. Elevated ET-1 is associated with
coronary inflammation and atherosclerotic plaque in
human coronary arteries, suggesting that it promotes plaque formation. Few studies have compared levels of ET-1
in patients with coronary artery disease (CAD) relative to
non-CAD patients [60]. It has recently been shown that
using an ET-1 antagonist, such as bosentan, during primary
PCI in STEMI patients may improve LVEF and tissue

192

perfusion [57]. The use of ET-1 antagonists might serve as

a protective adjunctive therapy for reperfusion of coronary
artery in acute MI patients [57, 61]. In patients with severe
heart disease, short-term infusion of bosentan has been
shown to increase cardiac index and reduce systemic and
pulmonary resistance, with no effect on heart rate [62].
Another study involved 36 patients who were classified as
NYHA functional class III with a mean EF of
22.4 4.5 %. Cardiac index and stroke volume was significantly increased in patients who received an ACE
inhibitor and bosentan compared with those who were
treated with an ACE inhibitor and placebo [62].
ET receptor blockade reduces progression of
atherosclerosis and improves coronary endothelial dysfunction in atherosclerotic hearts. Studies also show that
the timing of initiation of treatment is important. In an
animal model drug trial, treatment with a selective ETA-R
antagonist or nonselective antagonist was started 710 h
after coronary artery ligation, and the survival rate
increased from 43 to 85 %. In addition, LV remodeling
was improved, as shown by reduced scar area. However,
when treatment was initiated 48 h after ligation, LV
function deteriorated and the scar area was larger, suggesting that starting earlier treatment post-MI is more
beneficial. These findings in animal models must be taken
into consideration to determine a therapeutic window for
clinical trials. Overall findings indicate that ET-1 receptor
blockers (ET-1 antagonists) may limit MI vulnerability or
related morbidity [60].
3.6 Renin
Part of the pathophysiology of HF is the activation of the
RAAS, leading to sodium retention, vasoconstriction, and
volume expansion. Thus, blockade of the RAAS is a main
treatment strategy in the management of HF [6365].
ACE inhibitors and ARBs have demonstrated great
efficacy in the treatment of HF. However, long-term use of
these therapies causes a reflexive increase in renin, which
can overcome the effects of the angiotensin-targeted therapies and allows RAAS escape [61].
Direct renin inhibitor (DRI) therapy attempts to treat
this increase by binding directly to renin receptor sites.
ACE inhibitors and ARBs trigger an increase in plasma
renin concentration (PRC) and plasma renin activity
(PRA). In the RAAS cascade, renin converts
angiotensinogen to angiotensin I. ACE processes angiotensin I into angiotensin II, which is a powerful vasoconstrictor. Aldosterone release is also stimulated by
increased angiotensin II, which triggers reabsorption of
sodium and water via the kidneys [64]. By blocking renin
activity, DRI therapies could help strengthen RAAS
blockade in patients with HF [6365].

J. A. Iwaz et al.

The ALOFT (Aliskiren Observation of heart Failure

Treatment) study was one of the major trials to test the
first-in-class DRI, aliskiren, for efficacy, tolerability, and
safety in patients with chronic HF. ALOFT compared the
effects of the drug versus a placebo with concurrent ACE
inhibitor or ARB therapy. Aliskiren was found to be well
tolerated and suitable for daily single dosage. Significant
reduction of BNP and urinary aldosterone excretion was
also found in the treatment group versus the placebo group.
Additionally, echocardiography data showed improvement
in LV remodeling. However, adverse events commonly
associated with RAAS blockade strategies, including
hypotension, hyperkalemia, and renal dysfunction, were
found to be higher in the treatment group [64]. The
ALTITUDE (Aliskiren Trial In Type 2 Diabetes Using
Cardio-renal Disease Endpoints) study found both
increased occurrence of these events and increased rates of
non-fatal stroke among the treatment group, which resulted
in early termination of the study [66]. Subjects with diabetes and renal impairment experienced higher rates of
adverse events.
Currently, RAAS blockade for the treatment of chronic
HF with aliskiren and an ACE inhibitor or ARB needs
further examination focusing on efficacy and safety,
especially in patients with diabetes or renal impairment
[66].
3.7 Angiotensin Receptors and Neprilysin
Natriuretic peptides are endogenous hormones that help
maintain fluid homeostasis and sodium balance. Atrial
natriuretic peptide (ANP) is mainly secreted from the
cardiac atria in response to increased atrial pressure and
increased vascular volume. BNP is released from LV tissue
primarily in response to increased myocardial stretch,
which is a response to increased preload. Serum concentrations of ANP and BNP are elevated in patients with HF.
Neprilysin, a neutral endopeptidase, catalyzes the degradation of natriuretic peptides and is most commonly
expressed in the kidneys. Because it catalyzes natriuretic
peptides, neprilysin has been identified as a target in the
treatment of HF [67].
Clinical trials pairing a neprilysin inhibitor with an ACE
inhibitor have shown increased occurrence of angioedema,
making the combination less than ideal for RAAS blockade. LCZ696 (sacubitrilvalsartan), a first-in-class angiotensin receptor neprilysin inhibitor (ARNI), was developed
as a novel therapy that was found to cause less angioedema
than the ACE inhibitorneprilysin combination. LCZ696 is
a dual-crystalline complex drug comprising sacubitril, a
neprilysin inhibitor that decreases the degradation of
natriuretic peptides and prolongs their effects, and valsartan, an ARB that blocks the RAAS [68].

New Targets in Heart Failure

The PARAMOUNT (Prospective Comparison of ARNI

with ARB on Management of Heart Failure with Preserved
Ejection Fraction) trial assessed the effect of LCZ696 in
patients with HFpEF [67]. NT-proBNP was used as an
indicator of HF severity because it is not a substrate for
neprilysin. The study found that NT-proBNP was significantly reduced in the LCZ696 treatment group as compared
with the valsartan-only treatment arm. Additionally, the
LCZ696 group saw greater improvement in left atrial size
and NYHA class. LCZ696 was reported to be well tolerated, with no significant differences in adverse events
observed between the treatment groups. Another study, the
PARADIGM-HF (Prospective Comparison of ARNI with
ACE inhibitor to Determine Impact on Global Mortality
and Morbidity in Heart Failure), assessed whether LCZ696,
was more effective than an ACE inhibitor alone in patients
with HFrEF [69]. Preliminary results of the study indicate
significant reductions in HF hospitalizations, cardiovascular death, and all-cause mortality in the LCZ696 treatment
arm versus the ACE inhibitor treatment arm. After review
by the PARADIGM-HF data monitoring committee, the
trial was terminated early for efficacy.
Findings from the PARAMOUNT and PARADIGM-HF
trials suggest that LCZ696 is an effective treatment for HF.
Both studies showed that LCZ696 was well tolerated and
did not result in more adverse events than conventional
RAAS blockade.

4 Targeting the Heart Rate

4.1 Heart Rate
All myocardial tissue possesses the property of automaticity. In addition to their contractile function, they also
relay electrical signals to adjacent heart tissue in a regulated, periodic manner. The sinoatrial (SA) node is the
prevailing pacemaker of the heart at an intrinsic heart rate
of at least 60 beats per minute (bpm). The SA nodes
electrical activity comprises four phases. The pacemaker
myocytes that are downstream of the SA node have the
intrinsic ability to produce slow diastolic depolarization by
driving the resting membrane potential towards the
threshold necessary to reach the next action potential [70].
The SA node uses ionic currents along with funny currents
(If) to accomplish its automaticity. Phase 0 is initiated by
an influx of calcium, which causes depolarization of the
membrane from its resting potential of around -60 to
?20 mV. It is important to note that this upstroke is different from the action potentials of the atria or ventricles,
which is caused by an influx of sodium. The SA node lacks
both phases 1 and 2. Phase 3 consists of repolarization,
caused by an outward current of potassium. Lastly, phase 4

193

makes up the If, which is characterized by an influx of

sodium across the sarcolemma during voltages within the
diastolic range [61]. It is known as the funny current
because, unlike other cation channels in the heart, which
are normally activated when the membrane potential is
positive, the If channels are stimulated by a negatively
trending membrane potential.
The activation of this If channel during membrane
repolarization is essential to the periodicity of the action
potential because it drives the membrane potential back
towards activation of the cycle upon completion of the
previous cycle. The If is directly activated by intracellular
cyclic adenosine monophosphate (cAMP), causing the If
channel to open and drive the membrane potential away
from the diastolic voltage and towards threshold, at which
point calcium channels can be activated again. Adrenergic
agonists can indirectly increase the amount of cAMP and
therefore increase stimulation of the funny channels to
increase the rate of slow diastolic depolarization, increasing heart rate. The converse is true with antagonists of
cAMP.
The If is a target of therapeutic intervention for HF
because of the control it places on the periodicity of the
heart, thereby directly controlling heart rate. Myocardial
ischemia is directly correlated to the oxygen demand
placed on the heart. A lower heart rate will result in a lower
time averaged cardiac workload, decreasing demand
ischemia. Several studies have shown an increased risk of
HF among patients who have elevated heart rates.
Many drugs for HF have been sought to control heart
rate, most notably b-blockers, which decrease cAMP driven by beta-adrenergic stimulation. However, b-blockers,
are not cardio-selective and can have unintended side
effects by blocking beta-adrenergic receptors in the brain,
lungs, and vascular endothelium, leading to unintended
side effects such as hypotension, erectile dysfunction,
depression, and bronchospasm [71]. Ivabradine is more
cardio-selective because it inhibits the funny channel by
binding to the intracellular channel pore [72]. This inhibition occurs only when the funny channel is open because
it must have access to the channel pore itself before binding
and blocking. Its action is related to higher frequencies of
channel opening. Therefore, ivabradine is found to be
beneficial in patients with chronic HF because it is most
effective during times of tachycardia and demand ischemia
[70]. It is able to lower the firing rate of the SA node
pacemaker cells without impacting the length of the action
potential itself and ultimately is able to lead to substantial
heart rate reduction.
By significantly lowering heart rate, ivabradine has been
clinically shown to reduce major risks associated with
tachycardia in patients with chronic HF. Treatment with
ivabradine has been shown to reduce the resting heart rate

194

by 6 bpm from a baseline of 70 bpm. The BEAUTIFUL

trial, which assessed patients with LV systolic dysfunction
in the setting of stable CAD, showed that, while ivabradine
did not impact the adverse outcome of cardiovascular
death, it significantly reduced the rate of any coronary
event by 22 %, fatal and non-fatal MI by 36 %, and
coronary revascularization by 30 % [73]. The SHIFT study
showed that ivabradine administration significantly
reduced the risk of death from HF by 26 % within 3
months of starting treatment compared with current optimal medical management and placebo.
Unlike b-blockers, ivabradine does not alter myocardial
contractility or intra-cardiac conduction. Thus, it is an
alternative therapy that can reduce myocardial demand
while maintaining cardiac output. For patients who cannot
tolerate b-blockers or who are unable to achieve optimal
heart rate control with a b-blocker, ivabradine may be
preferable. It has been shown to decrease HF hospitalization and mortality from cardiovascular causes, and improve
patient quality of life. Side effects of ivabradine are
uncommon and include hypotension secondary to bradycardia and visual disturbances secondary to blocking retinal funny channels. These can be alleviated by dose
reduction or discontinuation [74]. Ivabradine was approved
by the US FDA for use in stable chronic HFrEF in April
2015.

J. A. Iwaz et al.

Statins, a standard form of cholesterol-lowering medication, act as ROCK inhibitors. Statins inhibit geranylgeranyl pyrophosphate, a phosphate necessary for the
activation of RhoA, which is one of the major components
for the activation of ROCK [79]. More investigation is
needed to map out the interactions between statins and
ROCK. In other studies, Y-27632, a cardiac ROCK inhibitor, has shown promise in treating cardiac diseases.
Various experiments have shown that Y-27632 helps normalize arterial pressure in animals with hypertension and
CHF, and decreases the amount of expression of smooth
muscle differentiation genes [80, 81]. Further research in
ROCK inhibitors has suggested that ROCK plays a crucial
role in cardiac hypertrophy and ventricular remodeling
after MI [82]. Additionally, fasudil, a pharmaceutical
ROCK inhibitor, has shown great promise in improving
motor loss in amyotrophic lateral sclerosis, pulmonary
hypertension, hypertrophy, apoptosis, and fibrosis [83, 84].
The given studies have shown that there may be a use for
ROCK inhibitors in HF therapy in the future. More
research focusing on the pathways of ROCK activity and
clinical use of ROCK inhibitors is needed.

6 Targeting the Nitric Oxide (NO) Pathway

6.1 Serelaxin

5 Targeting Myocardial Contraction

5.1 Rho-Kinase (ROCK)
Rho-kinase (ROCK) is an important cardiac effector
molecule that is expressed from early genetic development
and throughout adult life [75]. ROCK is associated with
stress fibers and focal adhesions by phosphorylating the
myosin light chains, the actin responsible for the binding of
myosin II, increasing contractions. ROCK 2 isoforms are
typically found in the brain and heart, originating from the
effectors RhoA and the GTPase, which are responsible for
signal transduction, protein biosynthesis, checkpoint verification in cell division, and translocation of proteins
throughout membrane [76]. ROCK activation has been
linked to the altering of cardiac myofilaments by troponin
phosphorylation. Research suggests that because ROCK
phosphorylates p190RhoGAP, a regulator of Rho, it prevents the active GAP activity in smooth muscle cells,
which could lead to a hyper-activation of Rho at specific
sites [77, 78]. This can lead to deleterious cardiac diseases,
including atherosclerosis, hypertension, pulmonary hypertension, and cardiac hypertrophy. Inhibitors of ROCK have
been seen to improve cardiovascular health.

Relaxin-2, a member of a seven-peptide family with nearly

identical structures, plays various roles in pregnancy and in
the cardiovascular system. It is an insulin-like peptide
consisting of two chains connected by three disulfide
bridges with 65 amino acids. Produced in the corpus
luteum, it was found as a mediator of pregnancy-related
hemodynamic effects and most notably facilitates vasodilation in the cardiovascular system and the kidneys [85].
Relaxin-2 produces nitric oxide (NO), which binds to
RXFP receptors on the surface of vascular smooth muscle
and causes vasodilation within minutes of administration.
Serelaxin (RLX030, Novartis) is a recombinant form of
the relaxin-2 hormone [86]. In a phase I safety and tolerability trial by Dschietzig et al. [87], 16 patients with
chronic systolic HF received infusions of serelaxin, ranging
from 10 to 960 lg/kg/day. Reduction of right atrial pressure, pulmonary capillary wedge pressure (PCWP), and
BNP levels were observed at lower doses of serelaxin
(10100 lg/kg/day), while the effect of serelaxin on the
cardiac index and systemic vascular resistance was seen
only at higher doses [87]. This result may be due to the
limited number of patients in the study [87].
In a phase II study, 234 patients with a systolic blood
pressure (SBP) [125 mmHg were enrolled within 16 h of

New Targets in Heart Failure

their clinical presentation and evaluated after each infusion

of increasing doses (10, 30, 100, and 250 lg/kg/day) at
multiple time points. In contrast to other AHF drug trials, it
has been shown that the most pronounced effects were
associated with the 30 lg/kg/day doses. There was significant improvement in dyspnea and a trend toward greater
resolution of congestion. This usually means shorter length
of hospital stay and perhaps less morbidity and mortality
for the patient [88].
In a phase III clinical trial, 1161 patients with ADHF
were randomized to receive serelaxin (30 lg/kg/day) or
placebo, with multiple evaluations of symptoms, signs,
and clinical outcomes at various time points. Significant
improvement was observed in dyspnea on day 5 as
measured by a visual analog scale (VAS). The average
length of stay in the hospital was also decreased in the
group that received serelaxin compared with the placebo
group. Based on this study, serelaxin resulted in symptomatic improvement in patients; however, it did not
improve either of the two secondary endpoints related to
re-hospitalization within 60 days [89]. The main adverse
effects of serelaxin were hypotension and decreased
renal function. Although the role of serelaxin in the
future treatment of HF remains unclear, there may be
valuable effects in patients presenting with HF, SBP
C125 mmHg, and mild to moderate renal impairment
[85].

7 Cyclic Guanosine Monophosphate (cGMP)

and Protein Kinase G
The pathophysiology of HFpEF is complex. Recent studies
have looked at cyclic guanosine monophosphate (cGMP) in
myocardial dysfunction. Increased inflammation due to
comorbidities results in increased production of reactive
oxygen species by endothelial cells. This results in
decreased NO availability, which lowers soluble guanylate
cyclase activity in cardiac myocytes. This in turn decreases
cGMP and protein kinase G (PKG) activity. Lower PKG
activity leads to hypophosphorylation of cardiac sarcomere
proteins, which leads to increased passive or resting tension
and stiffness. This results in decreased myocardial relaxation and eventually hypertrophy. Given this biochemical
pathway, cGMP and PKG have become possible targets for
HFpEF treatment [90, 91]. The rationale is that by
enhancing cGMP signaling, one can theoretically increase
PKG activity and phosphorylation of sarcomere proteins,
resulting in improved myocardial relaxation and decreased
hypertrophy.

195

8 Targeting Myocardial Remodeling

8.1 Neuregulin
Neuregulin (NRG)-1 is a protein that belongs to the epidermal growth factor family of ligands that act through the
ErbB family of tyrosine kinase receptors (ErbB2, ErbB2,
and ErbB4) to regulate morphogenesis of many tissues.
Nrg-1b works to trigger a cascade of cellular processes that
functions in endocardial-endothelial/cardiomyocyte interactions to regulate tissue organization and cell growth [92].
These actions are mediated by the NRG-1/ErbB signaling
pathway, which is a paracrine signaling system that stimulates cellular proliferation, differentiation, and survival of
cardiac myocytes.
NRG-1/ErbB signaling is accelerated in early HF, but it
is reduced significantly in the advanced stages of HF. It is
thought that decreasing ErbB signaling in the failing
myocardium accelerates apoptosis and worsening of HF
[93]. Recombinant NRG-1b has been shown to improve
cardiomyocyte function and cardiac remodeling in several
animal models of HF. The beneficial effects of NRG-1
treatment have been proposed to result from the reduction
of mitochondrial dysfunction, myocyte apoptosis, and
oxidative stress. Cardiac function and remodeling were
also improved in diabetic cardiomyopathy through
decreased fibrotic tissue deposition [94, 95].
Phase I studies have reported an improvement in cardiac
structure and function as assessed by magnetic resonance
imaging, in patients with systolic HF treated with Nrg-1b
for 10 and 90 days [92]. This peptide increased cardiac
output via a vasodilator effect [92, 94]. This therapy
involved prolonged infusion daily and induced considerable nausea in the patients. Phase II and III studies have
already been activated in China and Australia, but not in
the USA.
Although the drug appeared to improve cardiac structure
and function over a period of 90 days, there are several
limitations [92, 94]. First, the ErbB expression increased
the likelihood for tumor growth as observed in preclinical
studies. Next, altered behavioral changes were seen in mice
due to the overexpression of NRG-1b. Nevertheless, there
is still potential value in this therapy. The first human study
to be performed with NRG-1 beta in CHF patients showed
an increase in LVEF by 12 % and a decrease in pulmonary
artery wedge pressure and systemic vascular resistance
[96]. Another study using recombinant NRG-1 LVEF has
reported decreasing end systolic and diastolic volume [97].
Clinical studies are still in the process of evaluating the
effects of recombinant NRG-1b in chronic HF.

196

9 Pharmacogenomics
Gene therapy in the treatment of chronic HF is a strategy
that seeks to improve mechanical function of cardiac tissue
at the cellular level while avoiding the detrimental effects
that are associated with classical positive inotropes, such as
dobutamine and milrinone [98]. Gene therapy is delivered
directly to the target tissue via adeno-associated viral
vectors [99]. Currently, several targets are under examination for the treatment of HF such as ryanodine receptor
stabilizers and sarco-plasmic reticulum Ca2?-ATPase2a
(SERCA2a) [99].
9.1 Ryanodine Receptors
The ryanodine receptor specifically (RyR2) is a protein
predominately found in the cardiac muscles, functioning as a
mediator for the release of calcium ions from the sarcoplasmic reticulum. Calcium released from the ryanodine
receptor has been associated with regulation of production of
adenosine triphosphate (ATP) in the heart [100]. In failing
hearts, ryanodine becomes altered through hyperphosphorylation, sensitizing the channel and making it unstable. This
causes a calcium leakage from the sarcoplasmic reticulum,
resulting in weaker contractions [101, 102].
Studies have demonstrated a strong correlation between
RyR2 stabilization and reduction of sarcoplasmic reticulum
dysfunction, which would protect the heart from further
damage [103]. Two ryanodine receptor stabilizers, KN-3
and JTV519, stabilize RyR2 by binding and closing the
channel, preventing calcium from passing through. In
addition to reducing the calcium release, these stabilizers
seem to improve diastolic function [104, 105]. In HF
patients, the ryanodine receptor can cause the decay of
another specific channel-stabilizing protein called calstabin2 (FKBP12.6), which results in a disrupted binding
that causes the calcium leak. Hyperphosphorylation of
RyR2 and depletion of calstabin2 are inducers of atrial
fibrillation. A newer version of the drug 1,4-benzothiazepine (JTV519) stabilizes the protein calstabin2 for
RyR2, preventing the Ca2? leak, thus preventing potentially fatal arrhythmias [106, 107]. Although promising in
HF management, the side effects of JTV519 are still relatively unknown, which should be a focus of further
research.
9.2 SERCA2a
One of the more promising gene therapies targets the
SERCA2a system. In a highly simplified model, during
systole calcium is drawn into the cardiomyocyte mainly
from the sarcoplasmic reticulum via ryanodine receptors.
which triggers contraction of the myofilaments. During

J. A. Iwaz et al.

diastole, the majority of the calcium within the cell is

sequestered in the sarcoplasmic reticulum via SERCA2a.
Contractile force of the cardiomyocyte is highly dependent
on the influx of calcium from the sarcoplasmic reticulum
during systole. Impairment of SERCA2a results in an
inability to maintain the calcium gradient. This results in
prolonged relaxation times, increased wall stiffness, and
reduced systolic pressure [98, 99].
The CUPID (Calcium Upregulation by Percutaneous
Administration of Gene Therapy in Cardiac Disease) study
demonstrated the benefits and safe use of SERCA2a gene
therapy [100]. However, additional trials with greater
sample sizes are needed in order to definitively determine
the safety and efficacy of SERCA2a in the treatment of
chronic HF.

10 Discussion
Despite advancements in pharmacotherapy, there is still
high morbidity and mortality in the HF population. Readmissions for HF have also been a large financial burden on
our already strained health system. One of the ways to
decrease re-hospitalizations and improve morbidity and
mortality is to seek out new pharmacotherapy that targets
pathophysiologic mechanisms in HF ( Table 1).
HF is a complex disease with many underlying causes.
Thus, a myriad of biochemical and pathophysiologic
mechanisms are at play. There is currently a large unmet
need for targeted treatment specifically for HFpEF. Most of
the current medications used, such as b-blockers and ACE
inhibitors, have been shown to decrease mortality mainly in
the HFrEF patient population, but not necessarily the HFpEF
population. Understanding the pathophysiology is crucial to
continued development of novel medications (see Table 1
for a summary). For example, treatment targeted to cGMP or
PKG as discussed above could result in improved myocardial
relation and decreased hypertrophy. Eventually, this may
lead to a more personalized medicine, where each patient
would receive a unique set of medications based on the
underlying pathophysiology of their disease, despite having
the same diagnosis of HF. However, much research is necessary before this can be achieved.
Aside from researching novel biochemical targets,
another aspect of future HF treatment is utilizing our current tools in a more efficient manner. For example, much
work has looked at natriuretic peptides, such as BNP and
NTproBNP. Studies have found that both can be used for
diagnosis and prognosis in HF. However, some studies
have discussed using BNP- or NT-proBNP-guided therapy,
where one would titrate medications based on NP levels
[108110]. One meta-analysis evaluated the effect of NPguided treatment of HF on all-cause mortality. All-cause

New Targets in Heart Failure

197

Table 1 Summary of new pharmaceutical targets in chronic heart failure therapy and their functions
Target

Function

Candidate agent

Galectin-3

Immune response, inflammation, cell growth, cell differentiation, cardiac fibrosis and
remodeling

ST2

Modifies immunologic processes, inflammation, myocardial remodeling

Adrenomedullin

Copeptin

Decreases systemic vascular resistance, promotes natriuresis and diuresis,

autocrine/paracrine effector
Stress hormone, neuromodulator

Endothelin-1

Vasoconstrictor, pro-inflammatory mediator

Bosentan

Renin

Triggers reabsorption of Na? and water in the kidneys

Aliskiren

Neprilysin

Degrades natriuretic peptides

Sacubitril (a component of
LCZ696)

Tolvaptan

If

Controls heart rate

Ivabradine

Rho-kinase

Associated with stress fibers and focal adhesions

Fasudil, Y-27632

RXFP receptors

Vasodilation

Serelaxin

ErbB tyrosine kinase

receptors

Regulates morphogenesis and organization of many tissues, cell growth, differentiation,

survival of cardiac myocytes

Recombinant NRG-1b

Ryanodine receptors

Regulates heart contractility

JTV519

SERCA2a

Regulates heart contractility

SERCA2a gene therapy

cGMP

Myocardial relaxation and hypertrophy

Protein kinase G

Myocardial relaxation and hypertrophy

cGMP cyclic guanosine monophosphate, If funny current (pacemaker current), NRG neuregulin, RXFP relaxin family peptide, SERCA2a sarcoplasmic reticulum Ca2?-ATPase2a, ST2 interleukin 1 receptor like 1

mortality was significantly reduced by NP-guided treatment (HR 0.62; p = 0.004), and reduced HF and cardiovascular hospitalization. This may help physicians titrate
medications more effectively and could in theory lead to
fewer hospitalizations, readmissions, and decreased mortality [111, 112].
In summary, HF is a complex condition that affects
many individuals worldwide. Despite recent advances in
treatment, HF still accounts for a large number of hospitalizations and readmissions. Studies have found a mortality benefit with current pharmacotherapy, such as bblockers and ACE inhibitors, mainly in HFrEF. Similar
studies looking at HFpEF have shown mixed results. A
variety of intracellular pathways could serve as potential
targets for future pharmaceuticals. This can lead to more
personalized therapy and initiation of earlier treatment,
which can further decrease disease progression. These
therapies have the potential to drastically alter the way HF
is both treated and perceived.
Compliance with Ethical Standards
Funding

No funding was received in the writing of this review.

Conflicts of interest Alan Maisel is currently a consultant for

Spingotec and a speaker for Alere and Critical DX. He also conducts
research for Novartis, Alere, Abbott, and Roche. James Iwaz, Elizabeth Lee, Hermineh Aramin, Danilo Romero, Navaid Iqbal, Matt
Kawahara, Fatima Khusro, Brian Knight, Minal Patel, and Sumita

Sharma have no potential conflicts of interest that might be relevant to

the contents of this review.

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