Cardiovascular Journal of Africa: Vol 32 No 5 (SEPTEMBER/OCTOBER 2021)

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 32, No 5, September/October 2021 AFRICA 279 exclusively associated with severe disease. 6 A prospective observational study including 120 patients hospitalised with dengue in a tertiary centre in India showed that 12.5% had CV manifestations, includingbradyarrhythmia (6.6%), left ventricular systolic dysfunction (3.3%), pericardial effusion (1.6%) and atrial fibrillation (1.0%). Among those with bradyarrhythmia, sinus bradycardia was the most common form reported. Only one patient developed a heart rate of less than 40 beats per minute and required a transient pacemaker; in the rest of the cases, the evolution was uneventful, and abnormalities resolved within days. Similarly, in a prospective study of consecutive, serologically confirmed cases of dengue ( n = 220 with nine severe cases), up to 62.5% demonstrated electrocardiogram (ECG) changes (including T inversion, ST depression and bundle branch blocks) and 24% had echocardiographic findings consistent with myocarditis (chamber dilatation and motion abnormalities). 7-9 While previous reports suggest that 3.3 to 24% of hospitalised patients with dengue may present with myocarditis, the prevalence of CV manifestations in ambulatory patients has not been reported. Major limitations of previous studies include the lack of a standardised definition for CV involvement and the inclusion of exclusively hospitalised cases in which the disease had already progressed in severity. 9 There are no quality studies that evaluate the role of age and gender on the appearance of CV manifestations in dengue. Pathophysiology of cardiovascular involvement Both systemic CV injury (such as endothelial dysfunction and alterations in vascular permeability) and localised cardiac injury (including myocardial necrosis and inflammation) may contribute to the appearance of CV manifestations in dengue. 9,10 Understanding of dengue pathogenesis has been hindered by the lack of an animal model that accurately represents the increased capillary permeability and decreasing viral burden seen in patients. 2 Minor non-specific changes in histopathological studies of the microvasculature suggest that transient disruption in the function of the endothelial glycocalyx layer occurs. The glycocalyx functions as a molecular filter, selectively restricting molecules within the plasma according to their size and three-dimensional characteristics. 2 Hypo-albuminaemia and proteinuria are observed during dengue, which is consistent with a change in the filtration characteristics of the glycocalyx. Both the virus itself and dengue non-structural protein 1 (NS1) are known to adhere to heparan sulfate, a key structural element of the glycocalyx, and high-level early viraemia and NS1 antigenaemia have been associated with more severe clinical presentations. 2 Patientswith severe dengue are at higher riskof CV involvement than those who are asymptomatic or experiencing mild symptoms. It follows that the pathophysiological mechanisms of severe dengue likely have CV consequences. 7 NS1, which plays a crucial role in severe dengue, may have a role in CV involvement, accordingly. High circulating NS1 levels and hyaluronan (a component of the extracellular matrix) are indicative of perturbed endothelial intercellular junction and disease severity. 11 Other vascular anomalies found in severe dengue include alterations of actin filaments and vascular–endothelial cadherin, increased paracellular gaps and enhanced vascular permeability, which may explain vascular leakage and shock. 12 Common pathophysiological mechanisms of severe dengue and CV manifestations may include endothelial dysfunction, systemic hypoperfusion and systemic hypoxaemia. However, the specific mechanisms that are responsible for CV manifestations of dengue have not yet been fully described. Histology from endomyocardial biopsies in a patient with dengue myocarditis has been studied (Fig. 3). Necrosis of myocardial fibres, inflammatory cell infiltration, marked interstitial oedema and perivascular inflammatory infiltrate have been found. 13 However, it is not yet determined if dengue myocarditis is the result of a direct viral invasion of tissue or of the immunological response mediated by cytokines through complement activation. Clinical manifestations Clinical manifestations of dengue range from asymptomatic to mild and severe cases. The symptoms of dengue are comparable to a common cold and/or gastroenteritis. The syndrome starts abruptly with fever, headache, retro-orbital pain, muscle ache, arthralgia, vomiting, diarrhea and/or rashes. A small proportion of patients, usually less than 5%, progress to severe and life- threatening manifestations. 6,14 In severe forms, multiple organs and systems may be affected, with several reports describing encephalopathy, encephalitis, fulminant hepatitis, splenomegaly and ocular complications. 6,15-18 Fig. 3. Left ventricular endomyocardial biopsy (Masson 40×) shows necrosis of myocardial fibres (arrow in A) with inflammatory cell infiltration and marked interstitial oedema causing fibre separation (A), perivascular inflammatory infiltrate (arrow in B) with a necrotic fibre (B), and perivascular lymphocytic infiltrate (thick arrow in C), and vacuolisation of myocardial fibres corresponding to cellular oedema (narrow arrows in C). Reproduced with permission from reference 13.