Journal Reading Cardiac Manifestation in Dengue Infection (Nuriza)

1. RESOURCE PERSON : DR. dr. Soroy Lardo, SpPD. FINASIM
Division of Tropical Medicine and Infectious Diseases
Indonesia Army Central Hospital Gatot Soebroto
 Resource person : d. soroy lardo finasim
JOURNAL READING
Nuriza Karuniawan
PPDS Kardiologi FKUI

2. OUTLINE
 INTRODUCTION
 CARDIAC INVOLVEMENT
 VASCULAR INVOLVEMENT
 CARDIOVASCULAR THERAPEUTIC TARGET
 CONCLUSION

3. 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

4. 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

5. Classification System

6. Clinical Course of Dengue

7. 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

8. Functional Studies
 Dengue infection is associated with transient, self-limiting myocardial
dysfunction

9. Pathogenic Mechanism Cardiac
Dysfunction in Dengue
 In majority, direct viral invasion of cardiomyocytes is unlikely

10. 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

11. 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

12. Clinical Course of Dengue

14. VES and Altered Calcium Homeostasis
in Dengue
 Increased Calcium concentration during
diastolic phase in Dengue infection

15. Functional Studies

16. Pathological Studies
 Histopathological studies limited only in autopsy
studies
 Results : interstitial oedema, inflammation, and
myocardial necrosis fulminant myocarditis
 Dengue capsid protein was demonstrated to be
present in cardiomyocytes, interstitial cell,
myoblast
 another finding : clusters of viral particles were
identified inside cardiomyocytes widespread
necrosis and interstitial oedema

17. 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

18. Clinical Features of Vasculopathy
Increased permeability
Splanchnic Circulatory Changes
Bleeding

19. Increased Permeability
 Profound in children and young adult; lesser degree is difficult to identified
 strain gauge plethysmographyassess 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

20. 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 (mildsevere) and in primary, or
secondary infections, and start earlier than previously understood

21. 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)

22. 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)

23. 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 procoagulant
factors
 viral induction of plasminogen
 release of a heparin-like circulating anticoagulant from the microvascular
surface

24. 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.

25. Cardiovascular therapeutic targets
 No antiviral agents
 Supportive,cautious fluid resuscitationadequate 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(?)

26. 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

27. Conclusion
 Dengue is broad, ranging from myocardial impairment and arrhythmias to
vascular barrier dysfunction causing plasma leakage and haemodynamic
compromise.
 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