Short-term Effect of Sacubitril/Valsartan on Endothelial

Dysfunction and Arterial Stiffness in Patient with Chronic

Heart Failure

Disusun oleh:
Gabriella Fransisca Ong
Kevin Filbert
Lastry Depi Portuna S
Tamar Roganda Sitorus
Nuryani Nainggolan

Pembimbing : Dr. dr. Brama Ihsan Sazli, M.Ked(PD), Sp.PD, K-EMD

 Table of contents

01 Introduction 03 Results and Discussion

02 Method 04 Conclusion
 Introduction
Heart failure (HF) is a significant health issue, ranking as
the second leading cause of hospitalization among
individuals over 65, even with optimal treatment.
Approximately half of HF cases fall under HF with reduced
ejection fraction (HFrEF).
 Introduction
Endothelial dysfunction, marked by reduced nitric oxide
(NO) availability due to increased reactive oxygen species
(ROS) production, is common in HF and predicts major
cardiovascular events and mortality. Inflammation and
oxidative stress play pivotal roles in both HF and
endothelial dysfunction, attracting inflammatory cells and
impairing endothelium-dependent vasodilation.
 Introduction
Arterial stiffness, linked to angiotensin II activity and
inflammation, is an independent predictor of HF and
cardiovascular events, worsening endothelial dysfunction.

Sacubitril/Valsartan, an angiotensin receptor-neprilysin

inhibitor (ARNI), offers promising cardiovascular benefits,
including reduced CV mortality, hospitalization, and
improved cardiac function. It may also impact metabolic
and arrhythmic aspects of HF.
 Introduction
Despite some controversial data regarding its
effect on ventricular arrhythmias,
Sacubitril/Valsartan shows potential as a
protective agent against inflammation and
oxidative stress.
This study aims to explore Sacubitril/Valsartan's
impact on endothelial dysfunction and arterial
stiffness in HFrEF patients, both at baseline and after
6 months of treatment. Additionally, it investigates
oxidative stress levels, platelet activation, and their
correlation with arterial stiffness and endothelial
dysfunction.
 Method
A prospective study at Catanzaro University
Hospital analyzed 100 consecutive Caucasian
HFrEF patients (82 men, 18 women, mean age
69.7 ± 7.7) following specific inclusion criteria,
including age >18 years, LVEF < 35%, NYHA
class II or III, and symptomatic despite stable
ACE-I or ARB treatment. Patients received
Sacubitril/Valsartan per guidelines,
discontinuing previous ACE-I/ARB. Dosage
increased incrementally. Initial assessment and
subsequent evaluations were conducted. Ethical
approval was granted, and participants gave
informed consent following the Helsinki
Declaration.
 Method

Blood pressure was measured after 5 minutes

of rest, diagnosing arterial hypertension based
on SBP >140 mmHg and/or DBP > 90 mmHg.
Laboratory tests included glucose, insulin,
lipoprotein, creatinine, e-GFR, NT-proBNP,
sodium, potassium, and hs-CRP measurements.
Oxidative stress and platelet activation
biomarkers, as well as cytokines, were assessed
via specific assays.
 Method
Arterial stiffness and endothelial function were
evaluated using advanced techniques.
Statistical analyses involved paired tests, linear
regression, and multivariate models. Data were
analyzed for significant changes and
relationships between various parameters.
SPSS 20.0 software was employed for all
comparisons.

This comprehensive study aimed to investigate

the effects of Sacubitril/Valsartan treatment on
a range of clinical, laboratory, and vascular
parameters in HFrEF patients.
Result and
Discussion
 Result

The study included 100 outpatients with heart failure, with a

predominantly male population (82%), and a significant portion
had NYHA class II (43%) or class III (57%) heart failure. The
main causes of heart failure were ischemic heart disease (76%),
valvulopathies (30%), and arterial hypertension (84%).
Comorbidities included atrial fibrillation (32%), type 2 diabetes
(66%), chronic obstructive pulmonary disease (35%), and
dyslipidemia (87%). Medications included mineral receptor
agonists (MRA), with a 36% reduction in intake over the 6-month
follow-up.
 Result

At baseline, diabetic patients were treated with oral antidiabetic drugs (OADs)
and insulin, but insulin use decreased by 6 months. Improvements in
functional status were observed, with many patients shifting to NYHA class I
or II. Most patients started on the lowest dose of Sacubitril/Valsartan, with
some transitioning to higher doses.
 Result

After 6 months of Sacubitril/Valsartan treatment, significant improvements

were noted in various clinical and hemodynamic parameters, including
reduced heart rate, blood pressure, and inflammatory markers. Oxidative
stress and platelet activation markers also improved, and arterial stiffness
decreased, indicating improved endothelial function. Correlation analyses
revealed associations between these changes and various biomarkers, with
some predictors identified in multivariate analysis.
 Discussion

This discussion explores a pioneering study examining the

potential impact of Sacubitril/Valsartan, a medication combining
an Ang II receptor blocker and neprilysin inhibitor, on endothelial
function and arterial stiffness in patients with heart failure (HF).
The endothelium, a single layer of cells lining blood vessels,
plays a critical role in regulating vascular functions such as
clotting, leukocyte adhesion, platelet aggregation, and the balance
of vasoactive substances. Endothelium-derived nitric oxide (NO)
promotes vascular relaxation and inhibits platelet function.
 Discussion

Endothelial dysfunction, characterized by impaired vasodilation

and a pro-inflammatory state, is closely linked to cardiovascular
disease (CVD) and HF. This dysfunction affects both reduced and
preserved HF patients and is observed in various vascular beds.
Increased oxidative stress contributes to reduced NO availability
and endothelial dysfunction, which, in turn, affects arterial
stiffness—an independent predictor of CVD.
 Discussion

The study demonstrates that six months of Sacubitril/Valsartan

treatment resulted in improvements in endothelial dysfunction,
arterial stiffness, and various clinical parameters in symptomatic
HF patients with reduced ejection fraction (HFrEF). These
improvements were associated with reduced inflammation and
oxidative stress, partially attributed to the medication's ability to
block angiotensin II receptors and reduce pro-inflammatory
factors. Platelet activation, crucial in thrombotic events, also
decreased with treatment.
 Discussion
Sacubitril/Valsartan demonstrated significant potential in
improving vascular function, particularly endothelial function and
arterial stiffness, which are key predictors of cardiovascular
outcomes. These improvements were linked to reduced oxidative
stress and inflammation. The study's findings suggest a promising
role for Sacubitril/Valsartan in enhancing cardiovascular health in
HF patients, highlighting its potential therapeutic benefits.

Moreover, the study highlights improvements in metabolic

indices such as glucose levels and insulin resistance. Lower levels
of insulin-like growth factor-1 (IGF-1) and uric acid were
associated with better vascular function.
 Discussion
In conclusion, Sacubitril/Valsartan shows promise in enhancing
vascular function, particularly endothelial function and arterial
stiffness, in HF patients. These improvements are linked to
reduced oxidative stress and inflammation. The study's findings
suggest a potential therapeutic role for Sacubitril/Valsartan in
improving cardiovascular health in HF patients, emphasizing its
potential benefits in addressing a range of cardiovascular issues.
Discussion
 Conclusions
In conclusion, the present study strengthens scientific
evidence supporting the use of Sacubitril/Valsartan in
HFrEF patients and confirms its beneficial effects on
hemodynamic, clinical, biochemical and metabolic
profile. Moreover, the novelty of our study is that six
months treatment with Sacubitril/Valsartan is able to
improve endothelial dysfunction and arterial stiffness in
HFrEF patients, likely through the reduction of
oxidative stress, platelet activation and inflammation
biomarkers circulating levels with the improvement of
cardio-metabolic burden.
References
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