Bệnh cơ tim đái tháo đường GS nguyễn hải thuỷ

• Among all patients hospitalized for heart failure, 25% to 30% patient have DM as a comorbid condition • In large-scale mortality trials, in HF patients with systolic dysfunction, dia

GIỚI THIỆU

GIỚI THIỆU CÁC ĐỀ TÀI NGHIÊN CỨU KHOA HỌC TẠI HỘI NGHỊ NỘI KHOA TOÀN QUỐC TẠI THÀNH PHỐ HỒ CHÍ MINH THÁNG 7/ 2011

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Hue College of Medicine and Pharmacy

Vietnam

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DIABETIC CARDIOMYOPATHY

Prof Nguyen Hai Thuy MD, PhD Hue College of Medicine and PharmacyDEMA-CVN.COM

Congestive heart failure in diabetic patient without CAD and HTN HbA1c : 8%, BP: 110/70 mmHg

IVSd: 1.06 cm, IVSs: 1.23 cm

LA: 4.29 cm, LVMI :180 g/m2, EF :20.5%

What’s your diagnosis?

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• Diabetes is observed in 15% to 25% of HF

patients in major clinical trials

• Among all patients hospitalized for heart

failure, 25% to 30% patient have DM as a

comorbid condition

• In large-scale mortality trials, in HF patients with systolic dysfunction, diabetes was an independent risk factor for death.

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New England Journal of Medicine 1999; 341(12): 857-865DEMA-CVN.COM

 2.4-fold in diabetic men

 5-fold in diabetic women,

3 independent of coexisting

hypertension or

ischemic heart disease.

• SOLVD ( Studies of Left

more likely to die.

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DM and younger HF study

• Under 65 years old.

– Four fold in diabetic men

– Eight fold in diabetic women

• Gender-specific cardiovascular

protective effects can be considered to

be mitigated once overt diabetes

develops in women.

W H Wilson Tang, MD, and James B Young, MD

ENDOCRINOLOGY AND METABOLISM CLINICS OF NORTH AMERICA, VOLUME 30 • NUMBER 4 • DECEMBER 2001

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• Some diabetic patients do not have obvious

ischemic insults that lead to progressive HF.

• A number study challenged that Diabetic patients

may have more diffuse and severe coronary

insufficiency than nondiabetic patients.

• Every 1% increase in the baseline glycosylated

hemoglobin level translates into a 15% increase in

risk of developing HF

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• Leyden E.(1881) commented that HF was a

―frequent and noteworthy complication of diabetes mellitus‖

diabetes can be traced to an abnormality in

metabolism‖

cardiomyopathy ‘ after performing post mortem

studies in 4 diabetic patients with cardiac failure,

coronary and structural heart disease as possible aetiologies.

• Clinical Science (2009) 116, 741–760DEMA-CVN.COM

Diabetic cardiomyopathy is a unique entity, unassociated with coronary artery disease, characterized by diastolic dysfunction It is rarely clinically apparent

unless associated with hypertension

(Bell, Diabetes Care 1995)

Over 30 years ago 4 diabetic patients with CHF, normal coronary arteries, and no other etiologies were proposed as having diabetic cardiomyopathy

(Rubler et al , Am J Cardiol 1972)

Diastolic dysfunction can be recognized in type II diabetics, in the absence of

concomitant hypertension, in a proportion ranging from 30% to 60%

(Nicolino 1995, Di Bonito 1996, Poirier 2001)

Diabetic Cardiomyopathy

Clinical Evidence

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II STRUCTURAL FEATURES OF DIABETIC

CARDIOMYOPATHY AND THEIR

FUNCTIONAL RELEVANCE

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cardiomyocyte hypertrophy and interstitial fibrosis in all except two samples

mitochondrial degeneration and fatty infiltration of the myofibrils to contraction band formation, perivascular and interstitial oedema and myocytolysis

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Mild myocardial fibrosis stained with Masons trichrome

(A) Perivascular

fibrosis in diabetic heart

(B) Mild fibrosis

between myofibres.

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2.Myocardial microvessels

• A study of human diabetic myocardium found two characteristic abnormalities in myocardial capillaries:

• endothelial swelling and/or

• degeneration and thickening of the

capillary basement membrane

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Myocardial fragment stained with

hematoxylin and eosin shows arteriolar

Electronmicrograph of a myocardial capillary from a diabetic patient, demonstrating

luminal occlusion with basement membrane thickening

Diabetic cardiomyopathy Clinical Science (2009)116:741-760

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Changes in Myocardial Structure

Myocellular and Interstitial Fibrosis

(Devereux et al Circulation 2000)

HYPERGLICEMIA  Accumulation of AGEs

Disturbed Ca++ handling  Cross linking

of collagen  FIBROSIS  DIASTOLIC

DYSFUNCTION

Bell Diabetes Care 2003DEMA-CVN.COM

III.DEFINITION OF DIABETIC

A distinct entity characterized by the presence of abnormal myocardial performance or structure ,

in the absence of epicardial coronary artery

disease, hypertension and significant valvular

disease

Aneja Am J Med 2008

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Microvascular and tissue dysfunction in

Marwick, Heart 2004

DIABETIC CARDIOMYOPATHY (DCM) and

DIABETIC HEART DISEASE (DHD)

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IV Myocardial substrate metabolism

in the normal heart

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Stanley W C et al Physiol Rev 2005;85:1093-1129

©2005 by American Physiological Society

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The metabolic pathways in cardiomyocyte ADP, adenosine diphosphate; ATP,

adenosine triphosphate; FFA, free fatty acids; CPT-1, carnitine palmitoyl transferase-1.

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Glucose utilization in the cardiomyocyte.

Phosphofructokinase-1 (PFK1)pyruvate dehydrogenase (PDH)Pyruvate dehydrogenase kinase (PDK)

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Control of fatty acid (FA) delivery and

utilization in the cardiomyocyte.

Malonyl-CoA, inhibits CPT-1 and FA oxidation AMP-activated kinase (AMPK) inhibits ACC, relieves its inhibition on CPT-1, and promotes FA oxidation

Malonyl-CoA decarboxylase (MCD), through decreasing malonyl- CoA by

decarboxylating it to acetyl-CoA, enhances CPT-1 and FA oxidation

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Inhibition of glucose oxidation by FA utilization.

insulin receptor substrate (IRS) , protein kinase-B (PKB) pyruvate dehydrogenase (PDH), Phosphofructokinase-1 (PFK1),

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Cardiovascular targets and actions of insulin.

Muniyappa R et al Endocrine Reviews 2007;28:463-491

©2007 by Endocrine Society

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V.Pathophysiology of diabetic cardiomyopathy

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ROS : reactive oxygen species, PARP: poly(ADP-ribose) polmerase GAPDH: enzyme Glyceraldehyde-3 phosphate dehydrogenase

1.Hyperglycemia

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ROS and NO

• The elevation of ROS leads to cellular damage by

oxidation, disruption of vascular homoeostasis

through interference with NO and, most recently, by modulation of detrimental intracellular signalling

pathways

• ROS have been implicated in all stages of the

development of HF, from cardiac hypertrophy to

fibrosis, contractile dysfunction and failure.

• Increased ROS causes cardiac dysfunction by direct

[poly(ADP-ribose) polymerase] as well as by

promoting apoptosis. DEMA-CVN.COM

(Poly(ADP-ribose) polymerase)

• PARP enzymes are overactivated in diabetes as a

reparative response to ROS-induced oxidative damage

to DNA

• PARP inhibits GAPDH (glyceraldehyde- 3-phosphate

glycolytic intermediates, which inturn activate a series

of transducers which inflict tissue damage via AGE

formation and PKC (protein kinase C) activation

NF-κB (nuclear factor NF-κB) and inducing overexpression of

the vasoconstrictor ET (endothelin)-1 and its receptors

Protein Kinase C

Increased protein

kinase C activation

Increased cardiac hypertrophy;

increased extra cellular matrix; decreased SERCA 2a function

Impaired relaxation; increased ventricular stiffness

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Hexosamine pathway

Increased

hexosamine flux

Sp1- O -GluN acylation of transcription factors decreasing SERCA2a expression45

Prolonged calcium transients; impaired relaxation

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increased ventricular stiffness

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Advanced Glycation End Products (AGEs)

impaired ventricular filling

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Cardiovascular targets and actions of insulin.

Muniyappa R et al Endocrine Reviews 2007;28:463-491

©2007 by Endocrine Society

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FFA & insulin resistance

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Ceramide is a cardiotoxin

in lipotoxic cardiomyopathy

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Alternative pathways whereby compensatory hyperinsulinemia contributes to myocyte hypertrophy through the sympathetic nervous system activation and MAP kinase/ERK pathways at a time when insulin receptor mediated Akt-1 activation is impaired.DEMA-CVN.COM

Pathway-selective insulin resistance in PI3K signaling creates imbalance between prohypertensive and antihypertensive vascular actions of insulin

exacerbated by compensatory hyperinsulinemia.

Muniyappa R et al Endocrine Reviews 2007;28:463-491

©2007 by Endocrine Society

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Impact of Insulin Resistance on Myocardial Metabolism:

Importance of FF Acid Generation

Adapted from Oliver MF, Opie LH, Lancet 1994; 343: 155

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Renin Angiotensin Aldosterone System

RAS Cardiomyocyte hypertrophy and apoptosis

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Activation of the Renin-Angiotensin System

(RAS)

• The role of activation of the RAS in the development

of diabetic cardiomyopathy is well recognized.

• Angiotensin II receptor density and mRNA expression

• are elevated in the diabetic heart.

• Activation of the RAS during diabetes mellitus has

been shown to be associated with increased oxidative damage and cardiomyocyte and endothelial cell

apoptosis and necrosis in diabetic hearts, which

contributes to the increased interstitial fibrosis

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Abnormality in calcium homoeostasis

• Diabetes impairs sarcoplasmic reticular calcium pump activities , which reduces the rate of Ca++ removal

from the cytoplasm in diastole

• Such alterations may contribute to the increased

diastolic stiffness characteristic of diabetic

Endothelial dysfunction

Impaired endothelial NO production and increased vasoconstrictor prostaglandins, glycated proteins, endothelium adhesion molecules and platelet and vascular growth factors enhance vasomotor tone and vascular permeability and limit growth and

remodelling DEMA-CVN.COM

Medial vascular calcification in diabetes mellitus

Arterial stiffness

Increased central aortic pressure and left ventricular afterload and lowered central diastolic and coronary perfusion pressures, leading to subendocardial ischaemia and interstitial fibrosis.DEMA-CVN.COM

Autonomic neuropathy

CAN (cardiac autonomic neuropathy)

Decreased sympathetic/parasympathetic myocardial innervation with impaired coronary resistance vessel vasodilator response and impaired ventricular diastolic filling

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Study of heart rate variability (HRV) in

NTDong, NHThuy, HVMinh, LTB Thuận (2003-2005)

• Aldosterone-induced fibrosis

• Myofibroblast growth with interstitial and focal

perivascular accumulation of collagen.

• HIF-1/VEGF

• HIF-1α activation via hypoxia/free radicals induces

angiopoietin, PGF, PDGF-β and VEGF but, in

diabetes, VEGF and its receptors, VEGF-R1 and

VEGF-R2, are decreased significantly , leading to

impaired angiogenesis.

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Thiamine dificiency in diabetes

Essex UK study

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Mecanism of thiamine dificiency in diabetes…

… are excreted principally in the urine

Độ thanh thải Thiamine (ml/min) Nhóm n Median Range P Chứng 20 3.7 2.6 - 26.2 ĐTĐ týp 1 26 86.5 12.8 - 228.4 (P<0.001) ĐTĐ týp 2 49 59.8 1.4 - 256.6 (P<0.001)

Giá trị bình thường

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Hammes et al., Nature Medicine (2003) 9; 294-299

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LVMI of diabetic patient before and after treating with high doses of vitamin B1

(143 g/m2 vs 116 g/m2)

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VI Diagnosis of DCM

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Figure 2 Trans-mitral valve spectral Doppler flow pattern

in a normal subject (upper panel), in a patient with mild diastolic dysfunction

(abnormal relaxation; middle panel), and in a patient with severe (restrictive) diastolic dysfunction (lower panel) In the upper panel, the E/A wave ratio is approx 1.5 to 1.0, and in the middle panel

the E/A wave ratio is <1.0 In

the lower panel, the E/A wave ratio is abnormally high and A

wave velocity is very low.

1 DIASTOLIC DYSFUNCTION

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JACC 2006

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Normal diastolic function and diastolic dysfunction

(obesity) by tissue doppler echography

Raev D.C (1994) : diastolic dysfunction more frequent and early than systolic dysfunction in type 1 diabetic patients

Poirier P and al (2001) : study of diastolic dysfunction in diabetic patients without HTN showed that diabetic cardiopathy is special cardiomypathy, independent with CAD and HTN

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2 Left ventricular hypertrophy (LVH)

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LVMI in type 2 diabetic patients without HTN

Tran Thi Van Anh,Nguyen Hai Thuy, Nguyen Anh Vu (2006-2007)

Prevalence of LVH with LVMI ( male >125g/m2 and female > 110 g/m2) was 40%

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3 SYSTOLIC DYSFUNCTION

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4.TEI (Total ejection isovolumic ) INDEX

Christina Voulgari (2010) , Diabetic cardiomyopathy Vascular health and risk

management 2010:6 883-903 DEMA-CVN.COM

Echocardiography study of

39 non-hypertensive diabetic patients

• ( Nguyen Hai Thuy , Vo Thị Quynh Nhu , 2007-2008)

There was correlation between

(1) Tei index with duration of diabetes (r=0,243; p<0,05) and HbA1c (r=0,673 p<0,0001)

(2) LVMI with duration of diabetes (r=0,465;

p<0,01) and HbA1c (r=0,608; p<0,0001),

•

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5.Positron Emission Tomography (PET)

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MBF (ml/min/g)

Bellina et al., J Nucl Med 1990 ,

Positron Emission Tomography

“Technology of choise to assess microvascular function”

Quantitative Imaging of Microvascular Function

(Myocardial Blood Flow  MBF)

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Microvascular Dysfunction in Idiopathic DC

“… 75% of pts with microvascular dysfunction”

P = 0.0012 MBF < 1.36 MBF > 1.36

Patients with more Severe Microvascular Dysfunctionare at Increased Risk of Death and/or Heart Failure

Neglia et al., Circulation 2002

Dip MBF

< 1.36 ml/min/g

Increased relative risk of 3.5 times

in 5 yrs

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6.Cardiac biomarkers

• BNP is a cardiac hormone secreted in

response to ventricular volume and

pressure overload

• Although it is both sensitive and specific for congestive HF, it cannot reliably

distinguish between systolic and diastolic

HF, which limits its diagnostic use in

diabetic cardiomyopathy

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• Study of plasma NT-proBNP levels in 104 diabetic patients (Nguyen Hai Thuy, Le Thanh Tung, 2010)

• NT-proBNP levels of diabetic patients

• with and without LVH ( 279 ± 227,2 vs 45,72 ± 31,5 pg/ ml, p = 0,001 ).

• with and without diastolic dysfunction ( 286,19 ±

230,34 vs 48,44 ± 34,53 pg/ml, p = 0,001 )

• With and without systolic dysfunction ( 376,69 ±

299,4 vs 89,75 ± 91,8 pg/ml, p = 0,001 )

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STAGES OF DIABETIC CARDIOMYOPATHY

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VII.Management of Diabetic Cardiomyopathy

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Glycaemic control

• Hyperglycaemia increases the level of

FFA, oxidative stress,and growth factors, and causes abnormality in substrate

supply and utilisation

• Hence, diabetes control may be the most basic and important strategy for preventing the development of diabetic

cardiomyopathy

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Targets for glycemic (blood sugar) control in

most non-pregnant adults

• American Diabetes Association Diabetes Care 2010;33(suppl 1)

• Implementation Conference for ACE Outpatient Diabetes Mellitus Consensus Conference Recommendations: Position Statement

at http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf Accessed January 6, 2006

• AACE Diabetes Guidelines – 2002 Update Endocr Pract 2002;8(suppl 1):40-82.

*<6 for certain individualsGoals of Glucose Management

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