Introduction

Cilostazol, a type III phosphodiesterase (PDE3) inhibitor, has

both
- Antiplatelet function
- Vasodilating effects
It is mainly used to treat not only peripheral arterial disease
(PAD), but also used as an antiplatelet agent in patients
undergoing coronary stenting or carotid artery stenting.
Mechanism of action of Cilostazol
Inhibition of cyclic nucleotide PDE3
Subsequent elevation of intracellular cyclic adenosine
monophosphate (cAMP) levels.
The effects on left ventricular (LV) function were investigated
in a previous study, but there are no studies that show the
effects on right heart function and pulmonary artery pressure
(PAH)
Method
The study population consisted of 263 patients with newly diagnosed PAD
between March 2011 and December 2012.
Exclussion criteria :
1. History of LV and RV systolic dysfunction with an ejection fraction of <50%,
2. Prior myocardial infarction or coronary revascularization,
3. CAD > 50%,
4. Atrial fibrillation,
5. No tricuspid regurgitation
6. Chronic obstructive pulmonary disease or valvular disorders,
7. Critical limb ischemia
8. Patients under dialysis
9. Patients whose medical therapy was changed during the follow-up period
All patients had mild or moderate tricuspid regurgitation.
214 patients were finally excluded
9 patients were subsequently excluded because of the cessation of oral
administration of cilostazol.
Finally, 40 with normal LV ejection fraction and mild or moderate pulmonary
hypertension were included in the study.
Method
Daily dose of 200 mg cilostazol was administered orally for 6 months for
treatment of PAD.
HR (beats/min), SBP, DBP were measured before the index procedure and
at 6 months.
All patients included in the study were in sinus rhythm. Cardiac rhythm was
followed with monthly ECGs, and also their ECGs were evaluated after
complaints of palpitation to diagnose any severe arrhythmia episode.
Echocardiographic data were obtained before and 6 months after
administration of cilostazol.
RV function was measured using conventional echocardiography, TDI, and
2D-STE, also pulmonary artery pressure was measured with Doppler
echocardiography in patients with mild or moderate tricuspid regurgitation.
2D-STE : two dimension speckle tracking echocardiography
Echocardiography Exams
(All parameters measured 3 times and average value were used)
Conventional parameters:
Interventricular septal thickness (IVST), posterior wall
thickness (PWT), left ventricular end-diastolic diameter
(LVDd), left ventricular end-systolic diameter (LVDs), left
atrial dimension (LAD), left ventricular ejection fraction
(LVEF), Early diastolic peak flow velocity (E), late diastolic
peak flow velocity (A) and pulmonary velocity, Tricuspid
annular plane systolic excursion (TAPSE), Right ventricular
fractional area change (RVFAC), Pulmonary artery systolic
pressure (PASP) & estimated right atrial pressure (RAP).
Tissue Doppler Imaging :
early systolic tricuspid annular velocity (S), the early diastolic
tricuspid annular velocity (E), isovolumetric acceleration
(IVA), tricuspid E/E ratio
Echocardiography exam
2D Speckle-Tracking Strain Analysis
Peak longitudinal strain (PLS)
Statistical Analysis
Statistical analysis was performed using SPSS for Windows,
version 15.0
A paired Students t-test was used to compare continuous
variables between two groups.
Comparison of continuous variables with abnormal
distribution between two groups was performed by Wilcoxon
test.
A significant value of P < 0.05 was used
Results
Baseline


PLS (%)
Discussion PDE Family
A total of 11 PDE families have been identified, mainly stored in
endoplasmic reticulum, some exists in cytoplasm (free part).
The distribution varies across different tissue and cell types,
and most likely the different subcellular compartments.
Another important difference is their specificity for cAMP vs
cGMP
PDE3 inhibitors block PDE3 at myocardium and vascular tissue
and cause an elevation of cAMP, causing increased :
- Heart rate
- Myocardial contractility
- vasodilator effect

Cilostazol is known as a vasculary selective PDE3 inhibitor used
for PAD, it has some effect on myocardial functions
Discussion Study on Cilostazol
Yoshikawa et al.s(2011) studied effects of cilostazol to LV function.
LVEF, S, and peak strain increased significantly after cilostazol
administration (assessed by conventional echocardiography, TDI,
and 2D-STE).
Umazume et al.(2013) published a case report of severe LVOT
obstruction with sigmoidshaped IVS related to oral cilostazol
treatment.
One of the possible mechanisms of LVOT was positive inotropic
effect of cilostazol

In this study right ventricle PLS, TAPSE, IVA, and RVFAC were
analyzed.
All of these parameters increased significantly after cilostazol
administration. Improvement in right ventricular systolic function is
due to direct myocardial effect or due to vasodilation
S : Early systolic annular velocity IVA : Iso volumetric Acceleration RVFAC : RV Fractional Area Chance
Discussion - PAH
Pulmonary arterial hypertension is a progressive disease
leading to RV enlargement and hypertrophy, and ultimately
right-sided HF.
Prostacyclin analogs, endothelin receptor antagonists, and
phosphodiesterase type-V (PDEV) inhibitors are currently
approved to treat PAH.
Pulmonary vasorelaxation can be achieved with drugs that
increase pulmonary smooth muscle cAMP or cGMP.
The predominant pathway for inactivation of these cyclic
nucleotides in the pulmonary vasculature is via PDEIII and
PDEV.
Discussion PDE Inhibitor
PDE inhibitor result subsequent elevation of intracellular level
cAMP and cGMP and activating protein kinase A (PKA).
PKA prevents the activation of an enzyme (myosin light-chain
kinase), which is important in the contraction of smooth
muscle cells.
PDEIII inhibitors increased level of cAMP and NO at smooth
muscle cells, thereby exerting its vasodilatory effect.
Discussion
Cilostazol Effect on
Diastolic dysfunction of LV may be the main etiology of PH.
Therefore, the patient was categorized according to the
existence of diastolic dysfunction by the standard criteria.
After categorization, Reduction in pulmonary artery pressure
was similar in both groups. So the effect on pulmonary artery
pressure may be independent of its effect on LV diastolic
function.


Cilostazol does not affect the right ventricular diastolic
functions, according to no significant changes in E/A and E/E
ratio after cilostazol administration.
Discussion
Cilostazol Effect on (contd)
Cilostazol has been associated with increased :
- mean heart rate
- conductivity in the AV node
- ventricular premature beats
- nonsustained ventricular tachycardia

It (and possibly other PDE III inhibitors) can be associated with
risk of ventricular tachyarrhythmia and excessive mortality in
patients with reduced left ventricular function.

Therefore, it is contraindicated in patients with congestive heart
failure. (FDA)
But during follow up serious supraventricular and ventricular
arrhythmias were not observed in this study.
All the patients included in the study were normal LV ejection
fraction that may be the reason were not develop severe
arrhythmia
Limitations
Small sample size
(No label indication of cilostazol treatment of pulmonary
hypertension. The ethic committee was allowed us only to
investigate the patients whose already using cilostazol for
PAD)
Pulmonary artery pressure measurement technique.
(The diagnosis and the follow-up effects of cilostazol on
pulmonary artery pressure were carried out by
echocardiographic parameters instead of invasive
measurement)
No control group.
Conclusion
Cilostazol improved right ventricular systolic function and
reduced pulmonary artery pressure
Thankyou
Diagnosis of PAD
(1) typical or atypical symptoms at exercise in the lower leg
or foot with ABI < 0.9
(2) for the patients having an ABI between 0.91.3, ABI after
exercise lower than <0.9,
(3) Dupplex USG was performed for diagnosis of the patients
having ABI>1.3.
PDE Family

PDE-I Family - Site of Action

Examples of PDE- inhibitor (1-11)

Examples of PDE- inhibitor (1-11)

Dana Point Classification of
Pulmonary Hypertension (PH)
1) Pulmonary Arterial Hypertension (PAH)
2) Pulmonary Hypertension due to left heart disease
(PH-LHD)
3) Pulmonary hypertension due to lung diseases
and/or hypoxia
4) Chronic Thromboembolic pulmonary
hypertension (CTEPH)
5) Pulmonary Hypertension with unclear and/or
multifactorial mechanism
Right Heart Failure - Symtomps/Signs
Pathophysiology RHF
Hypotension Low output



Representative strain curves following MI derived from circumferential strain (top) and longitudinal strain analysis (bottom).
The infarcted apical anteroseptum exhibits biphasic strain curves (black) following circumferential and longitudinal strain analysis.
In contrast to peak circumferential strain, peak longitudinal strain is a positive strain value. AVC=Aortic valve closure.
Aarsther et al. Cardiovascular Ultrasound 2012 10:23 doi:10.1186/1476-7120-10-23
Non-Doppler radial 2D strain before (A) and after myocardial infarction (B).
See flattened postoperative curves particularly septal (red), anteroseptal (yellow)
and anterior (light blue).
Holinski et al. Cardiovascular Ultrasound 2011 9:15 doi:10.1186/1476-7120-9-15
A
B

A

B
Sigmoid-shaped IVS

Guideline ASE 2010 Right
Heart function
RV systolic function parameters

RVFAC

Barst RJ, Gibbs JS, Ghofrani HA, et al. Updated evidence-based treatment
algorithm in pulmonary arterial hypertension. J Am Coll Cardiol 2009;54:7884.
Contraindication Cilostazol
(FDA)
Cilostazol and several of its metabolites are
inhibitors of phosphodiesterase III. Several drugs
with this pharmacologic effect have caused
decreased survival compared to placebo in
patients with class III-IV congestive heart failure.
Cilostazol is contraindicated in patients with
congestive heart failure of any severity.
Autoregulation method by which
increased myocardial contractility with an increase in heart rate.

The inability of the Na+/K+-ATPase to keep up with influx of sodium at higher
heart rates. When a higher heart rate occurs, for example due to adrenergic
stimulation, the L Type Calcium channel has increased activity. The 3Na+/Ca++
exchanger (which allows 3 Na to flow down its gradient in exchange for 1 Ca++
ion to flow out of the cell) works to decrease the levels of intracellular calcium.
As the heart rate becomes more robust and the length of diastole decreases,
the Na+/K+-ATPase which removes the Na+ brought into the cell by the Na/Ca
exchanger does not keep up with the rate of Na influx. This leads to a less
efficient Na/Ca exchange since the gradient is decreasing for sodium and
therefore Ca++ builds up within the cell. This results in an accumulation of
calcium in the myocardial cell via the sodium calcium exchanger. And leads to a
greater state of inotropism, a mechanism which is also seen with cardiac
glycosides.

Alternatively, another mechanism is that the Na+-Ca++ membrane exchanger,
which operates continually, has less time to remove the Ca++ that arrives in the
cell because of the decreased length of diastole with positive chronotropy. With
an increased intracellular Ca++ concentration, there follows a positive inotropy
Treppe Phenomenon
The Bowditch effect