Early cardiovascular involvement in dengue fever: A prospective study with two-dimensional speckle tracking echocardiography

Abstract

Cardiac abnormalities in dengue infection have been conventionally identified by clinical manifestations. The primary objective of our prospective observational study was to assess true cardiovascular involvement and early myocarditis in 150 hospitalised, confirmed cases of dengue fever, through myocardial strain detection using two-dimensional speckle tracking echocardiography. Myocarditis was defined on the basis of European Society of Cardiology (ESC) 2013 criteria. Cardiac biomarkers, namely, creatine phosphokinase myocardial band was elevated in 28.6% and Troponin-T in 23.3% patients. Electrocardiography was abnormal in 64.6% while 6% patients had two-dimensional structural echocardiographic abnormalities. Myocardial dysfunction was suspected in 27.3% based on ESC criteria and strain analysis. The severe dengue group had lower longitudinal strain [−16.4 (6.3)] and circumferential strain [−15.7 (6.7)]. Two-dimensional speckle tracking echocardiography was found to be useful in improving the understanding of early myocardial mechanics in dengue fever.

Keywords

dengue fever cardiovascular diagnosis

Introduction

The incidence of dengue fever (DF) has been rising in most states of India, with a geographical shift from urban to peri-urban and rural areas, the spread being attributed to the interaction of host pathogen along with environmental changes, unplanned urbanisation and various population immunological factors.¹ According to the National Vector Borne Disease Control and Prevention (NVBDCP), India had 1,23,106 confirmed laboratory dengue cases till October in the year 2021.² Dengue infections vary from subclinical to symptomatic disease. The clinical presentation also varies depending on the strain of the virus along with the age and immune status of the host.³ While atypical manifestations can be explained on the basis of underlying host response, infections, co-infections or as a complication of profound shock.⁴

Cardiac involvement is common but an insufficiently detected atypical manifestation in dengue. Its incidence varies from 1.25 to 70% in various studies according to the diagnostic tests and criteria used.⁵ The spectrum of cardiac manifestations ranges from subtle changes on electrocardiography to life threatening hypotension and arrhythmias.^5,6 Though conventional two-dimensional echocardiography (2D-ECHO) has been used for detection of myocardial dysfunction, it has constraints, and is dependent on the preload or venous return and relies predominantly on the contraction and relaxation abnormalities (fractional shortening) of the ventricle.⁷ A low ejection fraction and a reduction in fractional shortening are signs of poor systolic function and this may also be dependent on the autonomic state, i.e. heart rate and the preload.⁸

Moreover, the data on the cardiac aspect in dengue are not widely researched with the most sensitive and non-invasive method of detection for myocarditis i.e. with the two-dimensional speckled tracking echocardiography. Subclinical changes in the function of left ventricle can be identified by quantification of myocardial strain which is expressed as a fraction or percentage change from the original dimension of the object. For the detection of subtle regional wall abnormalities by speckle echocardiography, variations in myocardial strain and reduction in longitudinal strain allows for a prompt diagnosis.⁹ Two-dimensional speckle tracking echocardiography (2D-STE) has recently emerged as a specific technique for swift bedside as well as for offline analysis of left ventricular (LV) strains in longitudinal, radial and circumferential directions.

Material and methods

Our prospective study was conducted in a tertiary care centre in Northern India after ethical clearance from the ethics committee of the institute. The study was extended from a period of January to December 2019. The confirmation of diagnosis of DF was made on the basis of suggestive symptoms or signs followed by positive testing by rapid diagnostic test (NS1 or IgM positive) and/or positive serology (IgM) by Enzyme Linked Immunosorbent Assay (ELISA). Age >18 years and only hospitalised confirmed cases of DF were considered for the study. Patients with pre-existing cardiac diseases, electrolyte abnormality, pregnant females and immuno-compromised patients were excluded. A written and informed consent was obtained from all patients prior to examination and investigations. Patients were examined for cardiac involvement by relevant history and complete cardiac examination. They were then subjected to investigations and classified on the basis of 2009 World Health Organisation (WHO) guidelines for DF.

Each patient was assessed for evidence of cardiac involvement by point-of care testing for cardiac biomarkers creatine phosphokinase myocardial band (CPK-MB) with a range twice the normal limit as a cut-off while and/or Troponin-T measured qualitatively with results given as positive or negative. All patients were subjected to 2D-STE to detect early myocardial involvement using Philips EPIQ-7C Model: GMDW 40761 Serial No. US215BO909 machine by a cardiologist The standard apical 4-chamber (AP-4), 3-chamber (AP-3), 2- chamber (AP-2) along with parasternal long axis view and parasternal short axis view (SAX) at mitral area, papillary muscles, apex were obtained. These views were used for calculation of ejection fraction by 2D-ECHO and 2D-STE. The longitudinal and circumferential strain were obtained from these views. M-mode 2D-ECHO was done to calculate ejection fraction. Global longitudinal strain (GLS) of ≤ −20.0 was considered significant.

According to the ESC criteria 2013, diagnosis of myocarditis requires ≥ 1 clinical presentation and ≥1 diagnostic criteria from various categories.¹⁰ If the patient is asymptomatic, ≥ 2 diagnostic criteria should be fulfilled. It encompass clinical features of (a) acute chest pain, pericarditic or pseudo-ischaemia, (b) new onset (upto 3 months) or worsening of : dyspnoea at rest or exercise, and/or fatigue, with or without left and/or right heart failure signs, (c) subacute or chronic (> 3 months) or worsening of: dyspnoea at rest or exercise, and/or fatigue, with or without left and/or right heart failure signs, (d) palpitations, and/or unexplained dysrrythmia symptoms and/or syncope, and/or aborted sudden cardiac death. (e) unexplained cardiogenic shock, along with diagnostic criteria of (1) Electrocardiography (ECG)/holter/stress test changes, (2) Myocardiocytolysis markers, (3) Functional or structural changes on cardiac imaging (angiography/echocardiography/cardiovascular magnetic resonance [CMR]/ECHO) and (4) Tissue characterisation by CMR

Descriptive statistics were obtained for all study variables. All categorical variables were compared using Chi-square and Fisher's exact test and continuous variables using Student's t-test All data has been expressed as mean and standard deviation (SD) and for statistical analysis, p-value <0.05 was considered statistically significant. Statistical analysis was done using the latest SPSS Version 24.0 (IBM® SPSS Statistics Inc., Chicago, Illinois, USA).

Results

A total of 150 patients with confirmed DF were enrolled for the study following inclusion and exclusion criteria. Patients were classified into three groups according to 2009 WHO classification for DF: (i) DF without warning signs (DWS -) was present in 28%, (ii) DF with warning signs (DWS + ) in 32% and (iii) Severe dengue in 42%.

There were 100 (66.7%) males; 21.3% had myocarditis with a mean (standard deviation) age of 39.7 (15.1) years, while only 6% of females with a lower mean age 36.8 (11.3) years. There was no significant difference in terms of myocarditis with gender (p- 0.07).

The age group ranged from 18 to 75 years. The majority (42.7%) were in the age group of 18–30 years as depicted in the histogram in Figure 1. Patients in the ranges of 18–30 years and 51–60 years had a statistical significance (p < 0.05) of having myocarditis.

Figure 1.

Histogram depicting the age-distribution of the study population.

The duration of hospital stay varied from 1 to 22 days, with lower duration 4.19 (2.3) in patients with myocardial involvement (p < 0.05). Table 1 depicts the baseline demographic profile and clinical features of the study population.

Table 1.

Baseline characteristics of the total population.

Characteristics	Total (n = 150)Mean (Standard deviation)	Myocarditis (n = 41)	Without myocarditis (n = 109)	P value*
		“a”	“b”
Age (years)	36.7 (14.3)	39.1 (14.4)	35.8 (14.2)	0.10
Males (years)	35.1 (14.5)	39.7 (15.1)	33.8 (13.8)	0.02
Females (years)	38.7 (13.6)	36.8 (11.3)	39.1 (14.0)	0.32
Duration of hospital stay (days)	5.1 (3.2)	4.1 (2.3)	5.5 (3.4)	0.01
Hypotension/ shock (%)	31.33	12.0	24.6	–
Shortness of breath (%)	10.7	2.0	10.0	–
Basal crepitations (%)	13.33	8.0	5.3	–
Heart failure (%)	2.6	1.3	1.3	–
Heart rate (beats/min)	96.0 (17.8)	98.7 (16.3)	95.1 (18.2)	0.13
Respiratory rate (per min)	18.2 (4.0)	17.4 (3.6)	18.5 (4.1)	0.80
Systolic Blood Pressure (mm Hg)	100.4 (17.6)	101.9 (16.9)	99.1 (17.7)	0.26
Mean Arterial Pressure (MAP)	74.8 (13.6)	76.4 (12.6)	74.2 (13.9)	0.19
Platelet count (thousand/mm³⁾	15.8 (22.2)	18.2 (24.7)	14.9 (21.1)	0.12
Haematocrit (%)	42.7 (8.6)	53.0 (3.8)	38.9 (6.4)	<0.0001
CPK-MB (U/L)	44.4 (17.3)	66 (14.9)	36.7 (10.6)	< 0.05
Troponin-T (positive in %)	20.6	20.0	1.3	–

*Student t-test for group (a) and (b).

Cardiac symptoms were observed in 46.1% patients, of whom 31.3% patients were in shock at admission, 10.7% patients had dyspnoea followed by palpitations in 2% patients and chest pain in 0.7%. On examination, 13.3% patients had basal crepitations and 2.6% had features of heart failure. The mean heart rate was higher in the study population 96.0 (17.8), more in patients with myocarditis (98.7 (16.3)). The systolic blood pressure was lower in patients with and without myocarditis [101.9 (16.9) vs. 99.1 (17.7)] and the mean arterial pressure was similar in the two groups [76.4 (12.6) vs. 74.2 (13.9)], although, none of them were statistically significant.

Investigations revealed a mean platelet count of 15.8 (22.2) with no significant difference between either group. While the haematocrit in the myocarditis group was higher [53.0 (3.8)], and showed a statistical significance with the cardiac manifestations in DF.

Cardiac enzymes, CPK-MB was raised in 28.6% patients (p < 0.05) while qualitative Troponin-T was positive in 20.6%.

The ECG was normal in 38% patients. Sinus tachycardia was present in 36% patients which was the most common ECG abnormality followed by non-specific ST-T changes (25.3%), low-voltage complexes (20.6%), sinus bradycardia (12%), poor R-wave progression (5.3%), wide QRS complex (2%), pathological Q-wave and ventricular premature beat (1.3%). Only one patient had second-degree atrioventricular (AV) block.

2D-ECHO parameters were assessed according to the severity of dengue. There was no significant difference in LV size in diastole or LV dimension in end-systole. The LV filling pressure also did not demonstrate any significant difference although it was higher in severe dengue [0.8 (0.1)]. In our study, no compelling difference was seen in the left atrial volume between the groups. Left ventricular ejection fraction (LVEF) in patients of severe dengue was reduced to 60.9 (6.1) compared from others while 3.4% patients had a LVEF ≤50% while majority, 24% patients had a preserved ejection fraction of >50% demonstrating a negative correlation of EF with severity of dengue and myocarditis as seen in Table 2.

Table 2.

Echocardiographic and strain parameters of the patients based on severity of dengue.

Parameter	DWS (-)(n = 41)	DWS (+)(n = 47)	Severe Dengue(n = 62)	P value*
Parameter	“a”	“b”	“c”	P value*
LVED (mm)	41.0 (6.1)	41.8 (6.3)	43.9 (6.6)	0.06
LVES (mm)	29.2 (5.3)	29.4 (4.9)	30.3 (5.0)	0.47
IVSED (mm)	9.5 (1.6)	9.2 (1.7)	9.6 (1.7)	0.43
Ao (mm)	27.6 (4.3)	29.0 (4.2)	28.3 (3.6)	0.24
LA (mm)	30.2 (4.1)	33.1 (10.4)	31.2 (4.0)	0.12
E/A (m/s)	0.7 (0.2)	0.7 (0.2)	0.8 (0.1)	0.31
LVEF (%)	61.2 (5.7)	62.2 (5.1)	60.9 (6.1)	0.46
Strain parameters
Longitudinal strain
AP 2	−18.8 (16.2)	−16.1 (5.8)	−16.9 (4.8)	0.38
AP 3	−15.9 (7.0)	−16.0 (5.3)	−15.8 (6.5)	0.98
AP 4	−17.6 (6.6)	−15.9 (7.4)	−17.8 (4.9)	0.29
GLS	−17.0 (3.6)	−16.3 (4.5)	−16.4 (6.3)	0.75
Circumferential strain
SAX – M	−16.2 (6.8)	−16.0 (6.5)	−17.5 (6.3)	0.42
SAX – A	−14.8 (7.5)	−15.4 (7.6)	−15.1 (7.5)	0.93
SAX – B	−15.0 (5.3)	−16.1 (6.5)	−16.7 (5.1)	0.34
GCS	−15.0 (6.0)	−15.6 (6.2)	−15.7 (6.7)	0.83

*One-way ANOVA test (between group a, b and c).

DWS(-): Dengue without warning signs; DWS ( + ): Dengue with warning signs; LVED: left ventricular end-diastolic dimension; LVES: left ventricular end-systolic dimension; IVSED: interventricular septal thickness in end-diastole; Ao: Aorta area; LA: left atrial area; E/A: peak transmitral flow velocity in early diastole (E), peak transmitral flow velocity in late diastole (A); LVEF: left ventricular ejection fraction; AP-2: apical 2-chamber; AP-3: apical 3-chamber; AP-4: apical 4 chamber; GLS: global longitudinal strain; SAX-M; parasternal short axis view at mid or papillary; SAX-A: apex; SAX-B: base; GCS: global circumferential strain.

All the patients underwent 2D-STE to measure the longitudinal strain which was measured in AP 2, AP 3 and AP 4. The global longitudinal strain (GLS) in severe dengue was similar to patients with DWS ( + ) [−16.4 (6.3) vs. −16.3 (4.5)] but did not demonstrate any significant difference (negative value indicates the percentage shortening during systole). Longitudinal strain in severe dengue group was lower in the AP 3 view [−15.8 (6.5)] compared from AP 2 and AP 4 views [−16.9 (4.8) and −17.8 (4.9)] respectively. There was no convincing difference between the three groups as demonstrated in Table 2 and Figure 2.

Figure 2.

Images depicting longitudinal strain in apical views AP 2, AP 3, AP 4 chambers and global longitudinal strain (GLS) in a patient of myocarditis with normal ejection fraction (>50%) along with the bull's eye plot (extreme right).

The global circumferential strain (GCS) was −15.7 (6.7) for the patients of severe dengue where the more negative −17.5 (6.3) measurement was found at the parasternal SAX at the mid or papillary muscle area. All the strains were more negative for males. Circumferential strain values at the mid area (SAX-M), apex (SAX-A) and base (SAX-B) were −17.5 (6.3), −15.1 (7.5) and −16.7 (5.1) respectively as seen in Table 2 and Figure 3.

Figure 3.

Images depicting circumferential strain in parasternal short axis view (SAX) at mid, apex, base and global circumferential strain (GCS) in a patient of myocarditis with normal ejection fraction with the bull's eye plot (extreme right).

Discussion

Cardiac complications in DF, formerly thought to be very rare, are now progressively seen and myocarditis is one of the common cardiac manifestation. The prevalence of dengue myocarditis is variable, since the patients are either asymptomatic or have vague symptoms. The prevalence of myocardial involvement in DF in our study was reported to be 27.3% on the basis of ESC criteria and 2D-STE possibly due to larger proportion of the patients in category of DWS ( + ) and severe dengue. Hypotension was predominant cardiac symptom which was transitory, since the patients were managed according to the current treatment aiming at judicious fluid replacement therpay.¹¹ Certain studies have shown that asymptomatic myocardial involvement is much more common, with most cases being self- limiting.¹² While some have linked myocarditis with increasing severity of dengue infection.¹³

Even though, cardiac biomarkers (CPK-MB and Troponin-T) are non-specific markers of cardiac involvement, they could be an independent marker of myocardial involvement as evident in our study group with myocarditis.¹⁴ Depressed myocardial function can be due to either direct effect of the dengue virus or cytokine-induced immune damage.¹⁵ This was not observed in previous reports, where only minor part of the population had raised cardiac biomarkers.^16,17

ECG abnormalities are common during DF which are mostly benign.¹⁸ The possible mechanisms are linked to altered autonomic tone, calcium homeostasis or subclinical myocardial involvement.^6,19 The most prevalent ECG abnormality in this study was sinus tachycardia; attributed to the presentation of patients in the febrile stage of DF, followed by non-specific ST-T changes. This was contradictory to other reports where sinus bradycardia was the commonest ECG abnormality.^16,17 Bradyarrhythmia is significant when it occurs in the critical phase, as hypovolemia is also a contributory factor. Although, it does not contribute to the severity of the illness.

Since the cardiac biomarkers and ECG are not specific for cardiac involvement and can be fluctuating, therefore, myocardial dysfunction was hardly evident on either clinical examination, ECG or biomarkers. Thus, these patients were subjected to conventional 2D-ECHO. The functional cardiac involvement of patient in DF depends on the pre-existing cardiac function, volume status and autonomic tone.¹⁹ In our study, there was no significant difference in LV dimensions in either systole or diastole, probably due to less severe plasma leakage or early treatment with fluid replacement. Patients of DWS (+) had larger left atrial (LA) volume, although the difference did not corelate with the severity if dengue infection. This was conflicting to the previous studies which revealed increased LA volume in DF patients with diastolic dysfunction.^6,20 The LV filling pressures were higher for the patients of severe dengue group, which was similar to prior reports, in patients of DF presenting with thrombocytopenia.²⁰

The LVEF in the severe dengue group was reduced compared from the other groups, although the difference was not statistically significant. Only 3.3% patients had LVEF ≤ 50%. As seen from earlier studies, LVEF was significantly lower in dengue hemorrhagic fever.²⁰ The possible underlying mechanism of reduced LVEF is immune-mediated although myocarditis can be contributory.²¹

As early myocardial involvement can be otherwise missed on conventional 2D-ECHO, we combined the ESC criteria with 2D-STE. 2D-STE was used to measure the LV strains, which are dependent on LV load. The principle aim for detection of asymptomatic myocarditis is ambiguous since both systolic and diastolic dysfunction may occur in myocarditis as a result of lower filling pressures during diastole. Sengupta et al. advised that 2D-STE can be a more sensitive tool for the detection of early myocardial involvement.²⁰

Patients of severe dengue had lower longitudinal strain in the AP 3 view while there was no significant difference in the AP 2, AP 4 views and GLS. Global longitudinal systolic myocardial strain correlates strongly with the degree of myocardial oedema.²² In a retrospective cohort study, from 45 patients of suspected acute myocarditis, patients with myocarditis had lower longitudinal strain. Løgstrup et al. concluded, that in patients with preserved LVEF, GLS added supportive information to clinical and conventional echocardiography.²³ Although, CMR is a better diagnostic modality, the cost factor remains a major drawback.

The GLS was lower for males (−16.3) compared from females (−17.1). According to Sugimoto et al. females had more negative longitudinal strain, i.e., higher percentage of systolic shortening of the ventricular chamber length in AP 4, AP 3 and AP 2 chambers.²⁴ However, in our study males were associated with higher strain values compared with females. The exact mechanism for this difference remains unclear.²⁵ Certain factors such as smaller body surface area, lower systolic blood pressure, LV mass of females have a more favourable effects on the LV systolic function. The smaller variations of the strain parameters between males and females would have less impact on diagnosis and treatment. On the other hand, circumferential strain in severe dengue patients was highest at the mid or papillary area followed by the base and the apex at the parasternal SAX. The GCS was lower in severe dengue, but it was not significantly significant. This was in contrast to the previous reports where more strain was observed at the apex followed by mid and the base respectively.²⁴ We investigated longitudinal and circumferential strains because of better reproducibility as evident by previous reports.²⁶ Although, myocarditis may not predict the mortality rate even in patients of severe dengue, larger studies are required for the same.

Conclusion

Cardiac involvement is an important and neglected complication of dengue infection and is an integral part of expanded dengue syndrome. The spectrum of cardiovascular manifestations in DF is broad and should not be overlooked. The ECG should be done in every patient with DF, especially in patients with inappropriate bradycardia or tachycardia for age, cardiac specific symptoms, high-risk groups such as elderly, and those with underlying heart disease. If abnormal, these patients should undergo cardiac enzymes estimation and echocardiographic imaging. Newer modalities such as CMR imaging have a greater sensitivity but have yet to be determined in respect of their scope for early detection of myocardial injury in viral myocarditis, where LV strain and strain rate may be promising diagnostic and prognostic tools, even in patients with preserved LVEF. Most importantly, 2D-STE can be used in predicting deterioration and overall event-free survival.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship and/or publication of this article.

Ethical considerations

Written and verbal informed consent was obtained from all the patients. The authors certify that they have obtained ethical clearance from local ethical committee (Institutional review board).

Authorship contribution statement

All the Authors have substantial contributions to Concept and design of the study, acquisition of data, analysis and interpretation of data; Drafting the article, revising it critically for important intellectual content; Final approval of the version to be published. The prominent roles of each author include the following:

Samiksha Gupta: Patient handling, literature research, procurement of data, data analysis and preparation of manuscript

Monica Gupta: Intellectual content, concept, design, clinical studies, literature research, data procurement, data analysis, manuscript preparation, editing and review

Jeet Ram Kashyap: Intellectual content, literature research, data acquisition, manuscript preparation, editing and review

Suraj Kumar Arora: Intellectual content, literature research, data acquisition, manuscript preparation, editing and review

All the authors took responsibility to ensure the integrity of the work. The manuscript has been read and approved by all the authors, the requirements for authorship as stated have been met, and that each author believes that the manuscript represents honest work.

ORCID iD

Monica Gupta

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