A Novel Marker of Persistent Left Ventricular

Systolic Dysfunction in Patients with

Peripartum Cardiomyopathy :
Monocyte Count to HDL Cholesterol Ratio

Rima Rinanty
Nina Tristina
Wednesday, 25th November 2020
INTRODUCTION
Might lead to several
complications,
even death
Peripartum Cardiomyopathy (PPCM) :
potentially life threatening
complication on pregnancy PPCM is also associated
with high likelihood of
recovery
(up to 41%)
Introduction
Predictors of persistent left ventricular dysfunction : lower baseline LV
Ejection Fraction(LVEF), older age, late diagnosis and
elevated plasma markers of inflammation

The ability to identify early predictors of prognosis is very important

Recently, Monocyte to HDL ratio (MHR) has emerged as a novel and

widely available inflammatory markers
Methods Follow up duration :
12 months after diagnosed
Study Population

Total of 64 patients: April 2009 - May 2017

PPCM :
- Unexplained heart failure Non
- LVEF < 45% Recovery Recovery
- presenting during End of pregnancy  first months
group group
after delivery
- Previously healthy women
1. History of cardiomyopathy
2. Severe organic
valvular heart disease
Exclusion Criteria 3. Significant CAD
4. Clinical conditions
that increase inflammatory
markers
5. No recorded laboratory
measurement on admission
Methods

• Hematological test
EDTA • Automated hematology
analyzer Sysmex XE 1200

• HDL-C Concentration 
Biochemical selective solubilization method
Analysis • Using Kyowa Medex
Statistical Analysis

Mann-Whitney U Square
The Shapiro Wilk’s Test Student’s t-test
Test

Univariate logistic
Fisher’s Exact test regression
analysis

P value < 0.05 was considered significant

Results
Among 64 patients  mean age at diagnosis : 29.2±6.0 years

Clinical presentation by New York Heart Association

(NYHA)

Class
ClassClass I
IV
III 3% 8%
26%
Class II
63%

Class I Class II Class III Class IV

Results
The mean follow up : 72.1±5.5 months

29(45.3%)
Recovery group 35(54.7%)
Non recovery group
Results
Characteristic Nonrecovery Recovery P value
group group
(n=35) (n=29)
Age at diagnosis 29.8±6.0 28.5±6.0 0.417
(years)(SD)
Hypertension 5(14.3%) 5(17.2) 0.746
n(%)
Dyslipidemia 8(23.5%) 3(10.3) 0.169
n(%)
CAD 0(0) 2(7.1) 0.124 Table 1
n(%) Baseline clinical and laboratory
characteristics of patients with
Diabetes 3(9.1) 0(0) 0.102 and without recovery of LVEF
n(%)
Family History 6(18.8) 1(3.6) 0.109
n(%)
Results
Characteristic Nonrecovery group Recovery group P value
(n=35) (n=29)

Triglyceride 136.0(88.0-180.0) 97(84.0-128.0) 0.049*

(mg/dl)
HDL-C 39.9±14.6 52.0±13.2 0.001*
(mg/dl)(SD)
CRP 6.2(2.4-19) 2.1(0.9-3.3) <0.001*
(mg/dl)
WBC(X103 µL) 8.3(7.2-10.5) 7.5(5.8-8.5) 0.021*
Monocyte 0.63±0.18 0.47±0.14 <0.001*
(X103 µL)
Normal Values :
Triglyceride : <150 mg/dL
Monocyte/HDL 15.5(10.8-28.5) 8.8(6.4-13.8) <0.001* HDL-C : > 60 mg/dL
ratio CRP : < 1.0 mg/L
LVEF baseline(%) 29.0(21.0-35.0) 36.0(33.5-39.5) <0.001* WBC : 4.0 -11.0 X103 µL
Monocyte : 0,18-0,62 x 109/L
Baseline clinical and laboratory characteristics of patients
Table 1 with and without recovery of LVEF
 Figure 1

The comparison between

recovery and non recovery
group according to
MHR values
Results
Variable OR 95% CI P value
HDL-C 0.938 0.899-0.979 0.003*
CRP 1.247 1.061-1.465 0.007*
WBC 1.407 1.077-1.839 0.012*
Monocyte 1.976 1.309-2.983 0.001*
Monocyte/HDL 1.198 1.069-1.343 0.002*
ratio
Table 2

Univariate logistic regression analyses for prediction on non recovery

Discussion
- The exact pathophysiological mechanism is still unknown 
increased oxidative stress and inflammation have been proposed

- Sarojini et al : baseline IL-6, CRP and TNF𝛼 were relevant to

mortality in PPCM
- Glecier et al : inflammatory process characterized by cytokine.
imbalance
- Sliwa et al : plasma marker of apoptosis was relevant to this
clinical course of PPCM
Discussion
• Under certain stimuli, circulating monocytes transform into
macrophages. Monocyte and Macrophage can trigger an
inflammatory cascade.
• On the other hand, HDL-C counteract this inflammatory effects

• The combination of these two parameters may be used to

establish patients at high risk for adverse outcomes and guiding
clinician for aggressive therapy
Conclusion
• Higher MHR levels were significantly associated with
persistent LV systolic dysfunction in PPCM

• MHR can be widely used in daily clinical practice for

prediction of LV recovery
THANK YOU
Slide PR JE
Is there any data about the incidence of Peripartum Cardiomyopathy
in Indonesia ?
dr. Coriejati Rita, SpPK(K)

Data in the US show the incidence of PPCM reaches one in

2,500 to 4,000 pregnancies

While data on the incidence in Indonesia are still unknown.

Data from the 2012 IDHS (Indonesian Demographic and Health Survey)
: heart failure, including PPCM, as the cause of a high maternal
mortality rate in Indonesia reaching 228 per 100,000 live births.
Is there any data about the incidence of Peripartum Cardiomyopathy
in Indonesia ?
dr. Coriejati Rita, SpPK(K)
Hasan Sadikin Hospital, Bandung :
from 1st January 2011 – 31st December 2013 showed that the incidence of PPCM was 2
6.23% out of 305 women with pregnancy or postpartum and
cardiovascular complications .

Soetomo general hospital, Surabaya :

from 2014-2015 showed that the incidence of PPCM was 1 per 166 live births,
with the mortality rate during hospitalization was 15,7%.

References :
Sasmaya, H., Indra, T., Hasan, M., Martanto, E. and Aprami, T., 2018. Hypertension in pregnancy as the most influential risk
factor for PPCM. British Journal of Cardiology.
Annualmeeting.conferenceseries.com. 2020. Peripartum Cardiomyopathy And Its Relationship With Preeclampsia
| Cardiologists 2017 | Conferenceseries Ltd. [online] Available at:
<https://annualmeeting.conferenceseries.com/cardiologists/abstract/2017/peripartum-cardiomyopathy-and-its-relationship-
with-preeclampsia> [Accessed 1 December 2020].
- Is there any other inflammatory marker for PPCM ?
dr. Leni Lismayanti, SpPK(K)

Erythrocyte Sedimentation Rate (ESR) : is a surrogate marker of

the acute phase reaction.
During an inflammatory reaction  the sedimentation rate is affected
by increasing concentrations of fibrinogen, the main clotting protein,
and alpha globulins. There are several studies that showed ESR w
as a significant predictor of heart failure after MI.

There are still no data about ESR as predictor of outcome in PPCM

C-Reactive Protein (CRP) : is an acute-phase protein recognizes a range of
pathogenic targets including membranes of apoptotic and reactive cells.
A study form Sarojini et al (India, 2013) : plasma markers of inflammation were
significantly elevated in PPCM patients and correlated with increased LV
dimensions and lower EF at presentation.
Baseline CRP, IL-6, TNF-α, and higher NYHA FC were the only predictors of
mortality.

 These results contribute to inflammation which may contribute to

the pathogenesis of PPCM and its complications 
Neutrophil to Lymphocyte ratio (NLR) : is an inflammatory biomarker
that can be used as an indicator of systemic inflammation. Numerous
inflammatory biomarkers are correlated with disease severity and prognosis
across throughout heart failure .
In the study from Gurkan (2017) showed that Elevated NLR and increased
LVESD were independent prognostic factors in predicting persistent LV
dysfunction in patients with PPCM.

The NLR might assist in identifying high risk patients with PPCM
Platelet to Lymphocyte Ratio (PLR) : used to perform complete blood counts, reflects
inflammation, atherosclerosis, and platelet activation.

Inflammation The mechanisms of the association

between PLR and AHF are unclear.
One possible mechanism : increased
Thrombosis inflammatory response.
The inflammatory response plays an
important role in the pathogenesis of
Atherogenesis AHF
Platelet to Lymphocyte ratio (PLR)

The combination of these parameters an elevated platelet count and decreased

lymphocyte count, which lead to an elevated PLR might therefore predict major
adverse outcomes in AHF.
There are still no study about PLR to predict outcome in PPCM.
Monocyte to lymphocyte ratio (MLR):
 
Inflammation is a shared mechanism in coronary artery disease (CAD)
and subsequent heart failure (HF)
Study from Gijsbert et al (USA, 2017) : MLR is related to HF markers and HF
hospitalizations during follow-up after Coronary artery graft, independent of NTproBNP.
This study therefore suggest a potential role for MLR alongside with NTproBNP.
In conclusion  MLR related significantly to HF markers in patients with CAD.
 

There are still no data about the role of MLR in PPCM

Monocyte to HDL ratio (MHR) : Monocytes are a major source of
proinflammatory species during atherogenesis. High-density
lipoprotein-cholesterol exhibits antiatherosclerotic effects by
neutralizing the proinflammatory and pro-oxidant effects of
monocytes via inhibiting the •
migration of macrophages and LDL oxidation .
Monocyte to HDL ratio (MHR)

Study from Ekizler F et al (Turkey, 2019) : average MHR values of the patients
with persistent LV systolic dysfunction were prominently higher than the
patients with LV recovery.
 This parameter may be used to establish patients at high risk for adverse
•
outcomes and guiding selection for the type of therapy in patients with
PPCM. 
What is the normal value of Absolute Monocyte
Count and CRP ?
 
Normal value of Absolute Monocyte Count :

Absolute monocytes per microliter of blood

Age range
(mcL)
 
Adults • 0.2 to 0.95 x 103

Infants from 6 months to 1 year 0.6 x 103

Children from 4 to 10 years 0.0 to 0.8 x 103

Normal value of CRP :  
• CRP clinical level is between 0.00 – 3.00 mg/L .
• Low Risk : 0 – 1.0 mg/L
• Moderate Risk : 1.00-3.00 mg/L
• High Risk : > 3.00 mg/L
References. :
• Sarojini A, Sai Ravi Shanker A, Anitha M. Inflammatory Markers-Serum Level of C-Reactive Protein, Tumor Necrotic Factor-α, and Interleu
kin-6 as Predictors of Outcome for Peripartum Cardiomyopathy. J Obstet Gynaecol India. 2013;63(4):234-239. doi:10.1007/s13224-013-0
428-9
• MedicineNet. 2020. C-Reactive Protein (CRP) Test: Normal And High Ranges, Treatment. [online] Available at: <https://www.medicinenet.
com/c-reactive_protein_test_crp/article.htm> [Accessed 28 November 2020].
• Cho JH, Cho HJ, Lee HY, et al. Neutrophil-Lymphocyte Ratio in Patients with Acute Heart Failure Predicts In-Hospital and Long-Term Mort
ality. J Clin Med. 2020;9(2):557. Published 2020 Feb 18. doi:10.3390/jcm9020557
• Gürkan U, Akgöz H, Aksoy Ş, Can Gürkan Ö, Osken A, Unal Dayi S, Oz D, Haci R. Value of the neutrophil-to-lymphocyte ratio in predictin
g left ventricular recovery in patients with peripartum cardiomyopathy. Wien Klin Wochenschr. 2017 Dec;129(23-24):893-899. doi: 10.1007
/s00508-017-1227-6. Epub 2017 Jul 12. PMID: 28702739.
• Ye, Gl., Chen, Q., Chen, X. et al. The prognostic role of platelet-to-lymphocyte ratio in patients with acute heart failure: A cohort study. Sci
Rep 9, 10639 (2019). https://doi.org/10.1038/s41598-019-47143-2
• https://www.researchgate.net/publication/318022699_Effect_of_Monocyte-to-Lymphocyte_Ratio_on_Heart_Failure_Characteristics_and_
Hospitalizations_in_a_Coronary_Angiography_Cohort
[accessed Nov 30 2020].
• Ganjali S, Gotto AM Jr, Ruscica M, Atkin SL, Butler AE, Banach M, Sahebkar A. Monocyte-to-HDL-cholesterol ratio as a prognostic marke
r in cardiovascular diseases. J Cell Physiol. 2018 Dec;233(12):9237-9246. doi: 10.1002/jcp.27028. Epub 2018 Aug 4. PMID: 30076716.
• Ekizler, F.A., Cay, S. A novel marker of persistent left ventricular systolic dysfunction in patients with peripartum cardiomyopathy: monocyt
e count- to- HDL cholesterol ratio.BMC Cardiovasc Disord 19, 114 (2019). https://doi.org/10.1186/s12872-019-1100-9

 
Slide Pendukung JE
Shapiro Wilk’s Test
• One of the most common normality test available
• To test normality of continuous data
• When P>0.005 : data is normally distributed
• It has more power to detect non-normality
Mann Whitney U Test

Two independent
Used to compare groups
differences but not normally
distributed.
Student’s t Test

To show how significant the difference

between groups

Testing about the mean of a

small sample
Fisher’s Exact Test

When we have two

nominal variables

to know whether the

proportions for one
variable are different
among values of the
other variable. 
Logistic Regression Analysis
Logistic regression is used to obtain odds ratio in the presence
of more than one variable  will model the chance of
an outcome based on individual characteristics

Univariate Regression Analysis

• One dependent variable and one independent variable

Mulrivariate Regression Analysis

• several variables to see if one or more of them are predictive of a
certain outcome
 European Heart Journal (2015) 36,
1090–1097
Sanghavi M, and Rutherford JK. Circulation. 2014;130: 1003-1008.
Two Hit Model as Patophysiology of PPCM
Patophysiology of PPCM

BMJ 2019;364:k5287
 Cytokine Impacts
on
Cardiomyocytes

Nature Reviews Cardiology

 volume 17, pages269–
285(2020
European Journal of Heart Failure (2018) 20, 445–459
Activated APC Leads to Cytokines Production

www.researchgate.net/publication/2682
56892_INNATE_AND_ADAPTIVE_IMMU
NE_RESPONSES_IN_VIRAL_AND_CHRO
NIC_INFLAMMATORY_DISEASES
HDL Structures
- High Density Lipoprotein
(HDL) is one of five major
group of Lipoproteins

- The smallest Lipoprotein

- particles
- High density 
- high proportion of protein

H. Nawawi et al. J Fundam Appl Sci. 2017,

9(6S), 298-315
HDL Functions

Reverse Cholesterol Transport

Anti Oxidant

Anti Inflammatory
HDL as an Anti Inflammatory Particles

 10.1016/j.pharmthera.2012.12.001
Normal HDL level
The ability of HDL to reduce inflammatory injury and
oxidant stress has been shown to reduce CVD risk

It has been suggested that the anti inflammatory status of HDL may be of
greater predictive value for CVD risk than HDL levels

Roger White, Samantha Giordano and Geeta Datta (March 29th 2017). Role of HDL-Associated Proteins and Lipids
in the Regulation of Inflammation, Advances in Lipoprotein Research, Turgay Isbir, IntechOpen, DOI: 10.5772/67141
Structures of VLDL, LDL and HDL

DOI:10.1177/1538574416628654
Small dense LDL
- subfraction of LDL
a. Has a long residence
time in plasma
b. Enhanced oxidizability
c. Arterial proteoglycan
binding

The Journal of Clinical Endocrinology &

Metabolism, Volume 88, Issue 10, 1 October
2003, Pages 4525–4532
Lipid Metabolism

https://www.researchgate.net/publication/278524013
Steroidogenesis

Available at:
<https://www.researchgate.net/
publication/317768851_Roles_of
_glucocorticoids_
https://www.researchgate.net/publication/49680527
Hematoanalyzer in Hasan Sadikin Hospital

Cytochemical reaction of
the cells with a specific
reagent, followed by a
fluorescence.
(flow cytometric
analysis)

Using Sysmex Hematology Analyzer XN-1000

Flow Cytometry in Hematoanalyzer

Cytometry : measurement of
the physico-chemical properties
of the cell

Flowcytometry : measurement
of the cells and other
particles in a flow
Flow Cytometry in Hematoanalyzer
HDL examination preparation

1. Fasting for at least 12 hours before venipuncture

2. Both Serum or Plasma can be used plasma more preferred
3. Specimen collection tube : Serum Separator Tube
4. Interfering factors : Hemolysis, Icteric, Lipemia
HDL Cholesterol analyzer in
Hasan Sadikin Hospital
• Automated HDL method 
Siemens Dimension EXL consists of 4 steps of chemical
reactions :
1. HDL, LDL, VLDL, Chylomicron Dextran Sulfate LDL, VLDL, non reactive
Chylomicrone + HDL
Magnesium Sulfate cholesterol ester

2. HDL cholesterol ester +H20 PEG

HDL Cholesterol+RCOOH

3. PEG Cholesterol oxidase

HDL cholesterol ester +O2 △4 Cholestenon+H2O2

4. Peroxidase
2 H2O2+4- Colour formation + 5 H20
aminoantipirin+HSDA+H++ H 0
Normal Laboratory Value

American Heart Association. "About

Cholesterol." Updated: Apr 2017.
The Prevalence of PPCM in Hasan Sadikin Hospital

140
Jurnal Kardiologi Indonesia • Vol. 36, No. 3 • Juli - September 2015
Gambar 1. Jumlah Penderita PPCM di RSHS 1Januari 2011- 31 Desember 2013
The Prevalence of PPCM in Hasan Sadikin Hospital

• The prevalence of PPCM in RSHS is 26.23% out of 305 women with pregnancy o
r postpartum and cardiovascular complications , with the majority (86.3%)was
NYHA functional class IV.

(J Kardiol Indones. 2015;36:138-44)

Circulation. 2016;133:1397–1409