RESOURCE PERSON : DR. dr. Soroy Lardo, SpPD. FINASIMDivision of Tropical Medicine and Infectious Diseases

Indonesia Army Central Hospital Gatot Soebroto

Resource person : d. soroy lardo finasim

JOURNAL READING

Nuriza KaruniawanPPDS Kardiologi FKUI

OUTLINE

INTRODUCTION

CARDIAC INVOLVEMENT

VASCULAR INVOLVEMENT

CARDIOVASCULAR THERAPEUTIC TARGET

CONCLUSION

Introduction

Dengue is currently one of the most important emerging infectious diseases in the world

Dengue virus (DENV 1-4), genus Flavivirus, family Flaviviridae

Dengue is transmitted by mosquitoes of the genus Aedes, reported in >100 countries,

High disease burden across South and Southeast Asia

Shock more frequent in children, bleeding and organ impairment more common in adults

Introduction

Mild disease severe(1–5%) organ impairment, bleeding, and plasma leakage (DSS)

The increase in capillary permeability is the best known cardiovascular complication associated with dengue

Other cardiac manifestations : rare fulminant myocarditis to more-common associations with functional myocardial impairment and arrhythmias

Classification System

Clinical Course of Dengue

Cardiac Involvement

Cardiac manifestation of Dengue : impairment myocardial function, arrhythmia, myocarditis

Myocarditis

Dengue Myocarditis

Dengue in elderly

Evidence of cardiac manifestations of Dengue in three perspective

Functional

ECG

Pathology

Functional Studies

Dengue infection is associated with transient, self-limiting myocardial dysfunction

Pathogenic Mechanism Cardiac Dysfunction in Dengue

In majority, direct viral invasion of cardiomyocytes is unlikely

Functional Studies

Fulminant dengue myocarditis might represent a separate phenomenon in which host genetics or increased cardiotropism of the virus allow widespread myocyte infection and damage

Reports of dengue epidemics

DENV 1-3

Primary or secondary DENV infection

Pericardium : dengue pericarditis, pericardial effusion

Increased plasma leakage

Less frequent

ECG Studies in Dengue Infection

ECG changes are often transient and non specific

Bradyarrhythmia : sinus bradycardia, first- and second degree AV Block, VES

Tachyarrhythmia : AF

Non specific ST-T changes

Occur during any phase of the disease and fairly common (30-44%)

Mechanism

Altered autonomic tone

Electrolyte and calcium derangements

Subclinical myocarditis

Clinical relevance remains speculative

Clinical Course of Dengue

VES and Altered Calcium Homeostasis in Dengue

Increased Calcium concentration during diastolic phase in Dengue infection

Functional Studies

Pathological Studies

Histopathological studies limited only in autopsystudies

Results : interstitial oedema, inflammation, andmyocardial necrosis fulminant myocarditis

Dengue capsid protein was demonstrated to bepresent in cardiomyocytes, interstitial cell,myoblast

another finding : clusters of viral particles were

identified inside cardiomyocytes widespreadnecrosis and interstitial oedema

Vascular Involvement

Increased systemic vascular permeability and plasma leakage critical determinant disease severity

Coagulopathy

Endothelial activation

soluble thrombomodulin,

intercellular adhesion molecule 1

vascular cell adhesion protein 1

E-selectin

Clinical Features of Vasculopathy

Increased permeability

Splanchnic Circulatory Changes

Bleeding

Increased Permeability

Profound in children and young adult; lesser degree is difficult to identified

strain gauge plethysmographyassess filtration capacity (Kf)an overall measure of microvascular permeability

A study in Vietnamese children with DSS or DHF without shock

increased Kf in both groups

individual’s compensatory reserve ability to upregulate homeostatic mechanisms to balance the intravascular volume loss

healthy children have higher Kf than healthy adults

higher number of developing capillaries more vulnerable to leakage than mature capillaries

Increased Permeability

evidence ultrasound study

transient increase in capillary permeability (febrile phase,day 2–3)

more common in secondary infections

Another study, similar proportion of patients with primary infections and those with secondary infections (32% and 40%, P = 0.69)

pleural effusions, ascites, and gallbladder wall oedema are commonly present during the critical phase of dengue and correlate with disease severity

plasma leakage seems to be broad (mildsevere) and in primary, or secondary infections, and start earlier than previously understood

Increased Permeability

Capillary leak in DENV infection is slow and persistent narrow pulse pressure

Pulse pressure < 20 mmHg + impaired perfusion DSS

Close observation for signs of plasma leakage is critical from the end of the febrile phase

haemoconcentration, determined by tracking changes in serial haematocrit measurements (insensitive)

Splanchnic Circulatory Dysfunction

An ultrasound study of 45 patients with dengue

a dilated portal vein with lower flow velocity

a higher congestion index

a smaller inferior vena cava in patients with DSS than in those with DF or DHF without shock

(hepatosplanchnic circulatory dysfunction)

Bleeding

Mucosal bleeding, skin pethecie, and bruishing

coagulation abnormalities evolve during the various phases of the infection and correlate with vascular leakage severity rather than bleeding

Mechanism

loss of anticoagulant proteins through capillaries leak

endothelial activation increased thrombomodulin and other procoagulantfactors

viral induction of plasminogen

release of a heparin-like circulating anticoagulant from the microvascular surface

Pathogenesis of Vasculopathy

viral and NS1 interactions with the surface glycocalyx layer

endothelial glycocalyx layer

negatively charged mesh of glycoproteins

Proteoglycans

glycosaminoglycans

glycocalyx layer : primary barrier to the movement of water and other molecules out of the microcirculation

NS1 + heparan sulfate (major glycosaminoglycan)disruption increased vascular permeability.

Cardiovascular therapeutic targets

No antiviral agents

Supportive,cautious fluid resuscitationadequate tissue perfusion during the critical period of capillary leakage

Rarely, inotropic support is required

No cardiac-specific treatments for dengue myocarditis

standard treatment for cardiac failure (β-blockers, angiotensin-converting-enzyme inhibitors, and diuretics

Antiviral and immunomodulatory treatments, interferon beta, corticosteroids, and intravenous immunoglobulins(?)

Cardiovascular therapeutic targets

No benefit with corticosteroids in order to modulate plasma leakage

A study of lovastatin in early dengue is ongoing in Vietnam

antiviral properties

stabilizing and anti-inflammatory effects on the endothelium

upregulation of endothelial nitric oxide synthase might help to restore endothelial function and microvascular tone and integrity

Conclusion

Dengue is broad, ranging from myocardial impairment and arrhythmias to vascular barrier dysfunction causing plasma leakage and haemodynamiccompromise.

Myocardial impairment can contribute to haemodynamic instability during the critical phase of capillary leakage.

Pathogenesis studies are needed to address the underlying mechanisms of capillary leak and endothelial dysfunction so that effective therapeutic targets can be identified

echocardiography should be performed in patients with dengue, particularly in those with severe disease and refractory shock