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%,

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 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