Cardiovascular involvement and manifestations of systemic Chikungunya virus infection: A systematic review

Background: In the last three years, chikungunya virus disease has been spreading, affecting particularly the Americas, producing more than two million cases. In this setting, not only new disease-related epidemiological patterns have been found, but also new clinical findings have been reported by different research groups. These include findings on the cardiovascular system, including clinical, electrocardiographic and echocardiographic alterations. No previous systemic reviews have been found in major databases about it. Methods: We performed a systematic review looking for reports about cardiovascular compromise during chikungunya disease. Cardiac compromise is not so common in isolated episodes; but countries where chikungunya virus is an epidemic should be well informed about this condition. We used 6 bibliographical databases as resources: Medline/Pubmed, Embase, ScienceDirect, ClinicalKey, Ovid and SciELO. Dengue reports on cardiovascular compromise were included as well, to compare both arbovirus’ organic compromises. Articles that delved mainly into the rheumatic articular and cutaneous complications were not considered, as they were not in line with the purpose of this study. The type of articles included were reviews, meta-analyses, case-controls, cohort studies, case reports and case series. This systematic review does not reach or performed a meta-analysis. Results: Originally based on 737 articles, our reviewed selected 40 articles with 54.2% at least mentioning CHIKV cardiovascular compromise within the systemic compromise. Cardiovascular manifestations can be considered common and have been reported in France, India, Sri Lanka, Malaysia, Colombia, Venezuela and USA, including mainly, but no limited to: hypotension, shock and circulatory collapse, Raynaud phenomenon, arrhythmias, murmurs, myocarditis, dilated cardiomyopathy, congestive insufficiency, heart failure and altered function profile (Troponins, CPK). Conclusions: Physicians should be encouraged to keep divulgating reports on the cardiovascular involvement of chikungunya virus disease, to raise awareness and ultimately encourage suitable diagnosis and intervention worldwide. More research about cardiovascular involvement and manifestations of systemic Chikungunya virus infection is urgently needed.


Introduction
Rationale Chikungunya virus (CHIKV) is an RNA-type arbovirus species that according to the International Committee on Taxonomy of Viruses (ICTV) belongs to the Togaviridae family and Alphavirus genus, along with more than 30 other pathogens for vertebrates and humans, causing a very broad spectrum of disease 1,2 . The word "Chikungunya" means "which contorts or bends up" in Makonde language from Tanzania and Mozambique, referring accurately to the difficulty in deambulation or walking of those affected 1,2 . Despite CHIKV first being documented in 1954 in Tanzania, Africa and subsequently Asia 1,3,4 , it was not until 2006 that CHIKV first alarmed the world for being a major public health concern. After an explosive epidemic outbreak in French island La Réunion, where 35% of the total population was infected over six months, CHIKV arrived to central France and extended to Germany, Italy, Norway, and Switzerland 1 . Later on, the virus hit North, Central and South America and brought with it the concept of a "self-limited febrile illness", a more benign type of infection with predominantly articular symptomatology 1,3-5 .
Alphaviruses can be separated into two phylogenetic categories: "Old World" viruses and "New World" viruses. "Old World" viruses such as CHIKV are known for their articular tropism and exanthematous febrile syndrome; and the "New World" viruses such as the western equine encephalitis and Venezuelan equine encephalitis viruses 1-3 have preference for nervous system stromal cells. CHIKV infection pathway in humans is shared with Dengue fever, and is caused by the biting of borne-arthropods from the Aedes mosquito family, Aedes aegypti and most recently Aedes albopictus 1 , the last one being essential to the wide geographic colonization process ever since a new mutation (A226V) in CHIKV has conferred the virus a better ability to replicate in this species. Ae. albopictus is more common in Asia, and has become worthy of mentioning in the Southeast of the United States and the Caribbean region 6 . CHIKV currently circulating in America seems to no longer be related to the African lineage, but to strains documented in Asia and the Phillipines 2,4 .
The transmission cycle, although originally merely sylvatic between primates and forest mosquitoes, has developed an alternate urban cycle involving humans 1,6 . Aedes as vectors are capable of spreading the virus after biting a viremic human, after which CHIKV replicates in salivary glands of the female mosquito and then a new bite of a healthy host takes place 6,7 . After the infectious bite, the incubation period of CHIKV ranges from 1-12 days before clinical onset of symptoms 1,6 . The appearance of clinical manifestations of the febrile syndrome coincides with viremia settling in during a period of 5-7 days, when viral load can be as high as 10 9 viral genome copies per milliliter 3 . Most recently, cases of vertical transmission have been reported, but it is indeed rare, and transmission through nursing has not been proven 1,6,8 .
Three stages of disease after the incubation period have been recognized 9 : • Acute (<3 weeks post-infection) • Post-acute or subacute (3 to 12 weeks post-infection) • Chronic (>12 weeks post-infection) Not every patient develops the full three stages, and at least a 20% of the infected population will not develop any symptoms at all, despite serological confirmation 3,9 . On the other hand, isolated cases have reported severe acute manifestations, far from the classic expected evolution of the disease, especially in areas with renowned late outbreaks such as India (2006) 1,10 , La Réunion and Mayotte (France, 2006) 9,11 , Malaysia (2008), Thailand (2008) 12,13 and South America (Colombia, Venezuela and later Brazil, from 2014 until now) 14,15 . As a result, some authors have started to classify the clinical progression of CHIKV into either classical, severe or neurological (neuro-chikungunya) 10,13 . The severe subtype of the disease contemplates an atypical systemic compromise, in which the liver, lungs, and even the eye are affected by the extra-articular intense inflammatory response 10,16,17 . Similarly, the involvement of the heart has often been fatal and worth highlighting in some reports [18][19][20][21][22] , but it has not been very largely discussed.
Characterizing potential systemic compromise due to CHIKV infection, especially cardiovascular, and characterizing manifestations and complications as a result, is essential in clinical practice. Here, identifying the febrile syndrome is particularly common on a daily basis and, coexists in a great proportion of patients with other morbidities and chronic conditions, that could easily trigger a more severe presentation and clinical picture of the disease 9,11,23 . No previous systematic reviews have been found in major databases about cardiovascular involvement and cardiovascular manifestations of chikungunya virus infection, which is the main focus of this article.

Amendments from Version 1
This new version considered interesting comments of one of the reviewers regarding multiple aspects related to the comparison with dengue cardiovascular compromise, myocarditis and rhythm alterations in chikungunya, as well to correct some missed points during the first version, attending most of the comments raised by one the reviewers. This version 2 also includes updated PRISMA guidelines, as displayed in Supplementary file 1 and Supplementary file 2. Furthermore the grant information has been amended to declare that no grants were involved in supporting this work.

Eligibility criteria
Any original studies that report cases with cardiovascular manifestations (acute and/or chronic) related to Chikungunya. We included studies published in English and Spanish. Eligible study designs were case-control, cohort studies, case reports and series of cases.

Information sources
The systematic review was conducted using six bibliographical databases (Medline/Pubmed, Embase, Elsevier, ClinicalKey, Ovid and SciELO) as resources.
Search strategy. To explore the extent by which this topic is currently represented in medical literature, searches were initiated with "Chikungunya AND Systemic AND Manifestations", "Chikungunya AND Heart" and "Chikungunya AND Cardiac". Given the lack of studies, we explored other options (such as "Chikungunya AND cardiac involvement" "Chikungunya AND cardiac complication" or "Chikungunya AND cardiovascular involvement" "Chikungunya AND cardiovascular complications" and Chikungunya AND Atypical manifestation/complications", among others), but to be more sensitive and to include all the possibly relevant studies related to our SR, we only included studies that had been found in our initial searches. Article language was limited to English and Spanish, and there was no limit set for time of publication, but searches concluded on November 1, 2016. Dengue reports on cardiovascular compromise were included as well, to compare between both arbovirus' organic compromise. Articles that delved mainly into the rheumatic articular and cutaneous complications were not considered, as they were not in line with the purpose of this study.

Study selection
The type of articles included were reviews, meta-analyses, casecontrols, cohort studies, case reports and case series.

Data collection
Data extraction from reports was done independently by two investigators. They checked for duplicates and were responsible for an initial quality screening of the studies.

Data items
During individual article assessment the variables for which data were sought included any cardiovascular manifestation associated with CHIKV infection, as well as any electrocardiographic, echocardiographic and related laboratory findings in patients during acute and/or chronic phases of Chikungunya disease.

Risk of bias in individual studies
Chikungunya is an emerging disease in the Americas and reemerging in the world, so there are a small number of studies addressing the cardiovascular manifestations (acute and/or chronic) related to Chikungunya. The risk of bias is discussed throughout the article.
To assess the quality of eligible studies critical appraisals specific to study design were completed by two independent reviewers.
We have compiled and submitted a complete review of CHIKV that includes the main facts about characterization, origin and transmission of the virus, epidemiology, pathogenesis, and clinical features of the classic and severe/atypical disease . It provides a clear focus  on the extra-articular and mainly cardiovascular manifestations  of the CHIKV infection, diagnosis of CHIKV-induced cardiomyopathy, management, prognosis, and differences from what can be  observed with Dengue virus (DENV) infection.

Study selection
The research initially rendered a total of 737 articles: duplicates across the databases and articles about other viruses were eliminated, unless they focused solely on cardiac compromise (Supplementary File 2). Finally, 40 articles were selected based on their relevance and pertinence of the title or abstract to the systemic compromise that was being evaluated, with 54.2% at least mentioning CHIKV cardiovascular compromise within the systemic compromise (Supplementary File 2).

Study characteristics
The frequency at which the rest of the organs systems are affected is shown in Table 1. The information on the role of the cardiovascular system during CHIKV infection is very scarce indeed; only 21.4% of the resulting articles focused solely and exclusively on the cardiovascular findings; the first publication on the topic was by Obeyeskere et al. and dates to 1972. In relation to extraarticular compromise of other organ systems besides cardiovascular, the most published were the nervous system -both central and peripheral-and secondary skin complications.
Clinical course. The acute stage extends from the first symptomatic day to the 21 st day and is characterized by an end-ofincubation sudden high fever (often above 39°C), headaches, myalgia and the insidious onset of typical symmetric, bilateral polyarthalgia (most frequently of small distal jointsphalanges, wrists, ankles), along with a typical maculopapular evanescent rash 1,3,9 . The location of the arthralgias tends to vary between individuals. There are rare descriptions in the literature of pain in the costochondral, hip and temporomandibular articulations 24 , so it may not be advisable to dismiss a CHIKV diagnosis if these pains are present. Palmo-plantar pruritus, photophobia, edema in the face and extremities and adenopathies have been also described, and benign and self-limited hemorrhagic manifestations are relatively common in children. Subsequently, by the end of the acute stage, asthenia and adynamia tends to appear 1,9 .
In the post-acute stage, from the first to the third month, all symptoms described above tend to vanish, except for some residual arthralgia, and some residual fever and adynamia. Extra-articular rheumatisms such as tenosynovitis, bursitis, tendinitis, worsening of osteoarthritis and even tunnel syndrome and Raynaud Reporting articles n () and % corresponded to the number of articles (out of the eligible n=40), that described the type of compromise (e.g. osteoarticular, cardiovascular, etc). The frequency of different organ-type of manifestations was classified as follows: extremely common (100-80%), very common (79-60%), common (59-40%), unusual (39-20%), rare (19-10%) and extremely rare if below 10%.
phenomenon have been reported 9 . Not every patient develops this phase, and degrees of severity and functional limitation will depend on patients' previous comorbidities, mainly musculoskeletal. Alternatively, other risk factors for being still symptomatic after the first month have been linked, for instance, to having poor rest during the acute phase, and females above the age of 40 are at major risk 1,9,11 .
Chronic CHIKV infection would be defined as a symptomatic period longer than three months and manifestations (continuous or episodic) that last for months, years or even a decade. Manifestations are the same as previously described in the post-acute phase, presenting as oscillating arthralgias over time with or without inflammatory signs until, according to natural history of the disease, the patient returns to the health state that they had before the infection. The degree of functional limitation may vary from little to moderate; leaving to a mean of 50% the most incapacitating and aggressive compromise 9 .
Atypical presentations. Atypical presentations of CHIKV infection can involve almost every organ system, as seen in Table 2. Even though the most common extra-articular manifestations reported in the literature involve the nervous system 25-27 and the eye 17 ; alterations in the gastrointestinal tract, liver 16 , kidney, muscles, mucous membranes and skin and hematologic cells have been evidenced, as well as in hemostasis and coagulation processes. Cardiovascular compromise is worthy of mentioning because of its usually fatal outcomes 10,28 . Infection can lead to cardiovascular manifestations, but in addition, patients with existing cardiovascular disease can deteriorate quickly, worsening the short-term prognosis; as it has been described with diabetes, lupus; or neurological, renal, pulmonary and cardiovascular insufficiency 9,11,23 . A common denominator of the 0.5% of patients who develop these systemic atypical patterns of disease is having some kind of predisposing condition, disease, or advanced age 9,16,24 . In retrospective records of severe cases reported by Economopolou A., et al. from La Réunion, 89% had previous medical conditions, 78% took medication before the disease (14% NSAIDS) and 14% were alcoholic 11,23 . Nevertheless, it is notable that risk of severe infection and compromise seems to increase in large outbreaks, as documented in India (2006), where only 25% of cases developed classical CHIKV; and 75% were severe cases where 60% of these had some degree of neurological compromise 10 .

Synthesis of results
Cardiovascular involvement. La Réunion reported an overall outbreak mortality of 10%; heart failure was the attributed cause in 15% of the cases, myocarditis and pericarditis in 5% and acute myocardial infarction in 2%; leaving a remarkable total of 22% mortality due to cardiovascular compromise 11,15 . Several similar past records raise concerns about a possible cardiac tropism of CHIKV, with clear evidence. CHIKV penetrates the myocytes and generates direct damage to the muscle fibers, meanwhile inflammatory response and infiltrate grows, leading to secondary damage by a hypersensitivity reaction and necrosis, but usually with no typical signs of infarction 20,22,30 . Furthermore, it has been proposed that these alterations are longstanding, and tend to make the cardiac tissue more vulnerable to recurrent damage from other microorganisms 20 and favor transition from myocarditis to dilated cardiomyopathy 30 . As has been mentioned, Obeyeskere et al in 1972 was the first group to make such reports and observed the CHIKV physiopathology at cardiovascular level.
Clinical cardiovascular progression pattern. A progression pattern has been identified and proposed, with three phases. Patients may follow the three phases strictly, or present a torpid evolution right to the last phase and skip the second one. Also, time of progression varies between individuals, depending on the severity of the initial cardiovascular injuries and previous comorbidities.
First is "pre-congestive or prodromal"; when isolated, not very specific electrocardiographic findings are detected (especially T wave abnormalities). Cardiomegaly can be detected with a simple thorax radiography or echocardiogram and gallop rhythm may be auscultated, but there are no visible cardiovascular symptoms. By this time (after 7 days), the initial viremia peak is over, but we are in front of an incipient heart failure 19 .
The most documented electrocardiographic changes were T wave inversion in DII, III, aVF and V5-V6, and ST elevation 18,23,28,29 . These are relatively nonspecific findings, which are encouraged to be interpreted within the whole clinical context so that other compatible differential diagnoses such as acute coronary syndrome, electrolyte disorder, or even digitalis intoxication, can be dismissed 20 . In addition, echocardiograms mostly reveal biventricular hypertrophy and dyskinesia of wall movements; and these results are compatible with myocarditis. Ejection fraction may be mildly diminished and pericardial effusion is rare. Creatine Phospho-Kinase (CPK) levels may be increased after the first phase 28 .
The second phase is known as the "arrhythmic phase". It starts when the recent myocardial injury can no longer permit an adequate functioning of the cardiac conduction system. Again, according to the severity, findings may range from premature auricular and ventricular extrasystoles to atrial fibrillation with high risk of thromboembolism; and in the worst-case scenario, ventricular fibrillation and sudden death 19 . This wide spectrum directly correlates with the symptoms and hemodynamic state of the patient 31 .
The patients after the acute and subacute phase that are most affected will invariably develop heart failure, displaying some a right side insufficiency with pulmonary and peripheral edema and hepatomegaly; but more frequently a left side insufficiency with low perfusion and shock clinic 19 . Reduced peripheral blood flow can be responsible for many pathological events too, blurring the line between expected consequences of shock and the real direct organ damage of CHIKV. Kidneys are an example, as in Economopolou et al's retrospective study, 20% of the patients with heart failure also presented with pre-renal failure 23 , which suggests it is more of a consequence of shock in this instance. In contrast, lesions such as nephritis are more likely to be caused by the virus. Additionally, in this third stage, a constrictive syndrome has also been described, with extensive compromise and pericarditis, but it is indeed less common 24 . A summary of most the common clinical manifestations during CHIKV infection that suggest cardiac viral compromise is given in Table 3. Isolated signs and symptoms reported in single case reports that seemed to relate more to the pre-morbidities of the patient were excluded. Regarding blood pressure, there are significant variations in the reports, but recently hypotension was reported during acute CHIKV infection in patients with high blood pressure undergoing antihypertensive treatment. A pattern through the revised articles could not be identified, so having hypo or hypertension may be a poor predictor of cardiac compromise during CHIKV infection and seems more a product of the severity of the case and the numbers previously managed by the patient 20 .

Diagnosis and management of CHIKV infection with cardiac compromise.
Diagnosis of a CHIKV infection with cardiac compromise must be more epidemiological and clinical based rather than anything else. Specific CHIKV infection during acute phase could be diagnosed by molecular techniques such as PCR, but the phases that follow must be diagnosed by immunological/ serological tests, particularly the detection of IgG anti-CHIKV. Once CHIKV infection is suspected, echocardiographic imaging, MRI and other paraclinical exams will only help in assessing the severity of the damage. There is an evident lack of studies on the topic and therefore, lack of data determining sensibility and specificity of the findings that are mentioned in Table 3. However, imaging 18,21 . By now, it is evident that there are three clear, different outcomes to CHIKV infection: • Asymptomatic with no imaging sequelae; • Asymptomatic with partial reversion of EKG and echocardiogram changes; • Death Changes seen on cardiac magnetic resonance imaging that persist for more than one year from disease onset will be permanent and affect the patients to some degree later in life 18 . Simon et al thus proposes that in upcoming years, countries that suffered outbreaks of CHIKV since 2005, will see a long-term increase in dilated cardiomyopathy, reporting this as the most frequent sequelae, even in asymptomatic patients who had an apparently classic clinical picture involving arthralgia predominantly 18 . This raises public health concerns and the risk of a noticeable limitation in quality of life for these patients in the future.

Similar reports and findings on Dengue fever: Arbovirus-induced cardiopathy.
The cardiac tropism of CHIKV seems to be shared with DENV, with multiple cases in the literature displaying similar cardiovascular complications and often mimicking acute myocardial infarction as well 33,34 . Myocarditis is reported similarly. However, arrhythmias and compromise of the electric conduction system of the heart have a higher incidence with DENV, including supraventricular arrhythmias such as atrial fibrillation, atrioventricular (AV) blockage 28 and cases reporting refractory ventricular fibrillation as the ultimate cause of death 34 . Acute pericardial and pulmonary edema are also described, but the outcome is rarely fatal. As a common denominator in the published literature, most reports of cardiac involvement are seen in patients with hemorrhagic fever manifestations of CHIKV infection.

Physiopathology
Even though the etiological agent is very similar, DENV-induced cardiomyopathy has a variant: the plasma leak syndrome and characteristically endothelial dysfunction of DENV that may result helpful to the extravasation process and chemotaxis of inflammatory cells to myocardial tissue, creating a highly cytokine rich environment 35 , besides the already known tropism of DENV for the heart. This could explain why cardiovascular manifestations are much more common with DENV than with CHIKV 35,36 . Host susceptibility and the virulence of the strain also play a role in the severity of the clinical picture 37 . Nevertheless, what is noticed is that diagnoses are rarely made, interventions tend to be delayed and insufficient, and outcome is often an imminent refractory heart failure. Management has mostly been ineffective in containing the damage, and death by cardiac arrest becomes inevitable. Cases as severe as a 63-year-old woman with a T wave inversion in V5-V6 and global progressive hypokinesia have been reported. She experienced cardiac arrest and died 4 hours after admission 25 , where action time was so limited and management was not even mentioned 29 . It is not possible to state the standard management process for cardiac compromise from CHIKV infection due to the low frequency of reports of this type of CHIKV disease, so the only possibility available is to analyse management given to past reported cases in the literature and compare outcomes.

Electrocardiography and echocardiography
On the other hand, the treatment given to a successful case in India who remained fully asymptomatic after follow ups consisted of inotropic support (dopamine and dobutamine) and levocarnitine used to relieve mitochondrial dysfunction. Additionally, a 19-yearold male who was previously healthy developed myocarditis but was discharged after 3 days with Acebutolol and Ramipril, and at follow-up, premature beats had disappeared 22 . There is another case of a 21-year old woman who returned from La Reunion and responded clinically to with high doses of aspirin, and her EKG changes reverted 18 . Such good prognosis as seen in the aforementioned cases may not be representative of the true clinical progression, and may be biased due to the early age of the patients 28 .
In summary, management of CHIKV disease is not established everywhere, remains very variable, and consists mainly in correcting the clinical features of the cardiac failure, but does not taking into consideration the root cause. Beta-adrenergic blockers, ACE-inhibitors and inotropic support during the crisis are commonly reported in order to maintain hemodynamic stability. Only one case reported the use of prednisolone 21 , but without any other cardiac support drugs, and the outcome was equally poor. Studies on the impact of anti-inflammatory corticosteroids along with cardiovascular support drugs should be carried out, it seems to be a promising option considering the underlying severe systemic inflammatory response in these cases. A very similar substrate is seen in the eosinophilic myocarditis that can cause Toxocara canis, where early prednisolone in doses of 1mg/kg/day for the acute phase and 5-10mg/kg/day for maintenance has been recommended 32 .
Prognosis and functional sequelae. Ongoing studies should focus on determining the potential chronic cardiovascular outcomes that could develop in patients infected with chikungunya, in order to provide an appropriate early clinical intervention strategy to avoid potential disabilities.

Management
Management of DENV is poorly reported and not established everywhere, as is the case with CHIKV. Early use of IV hydrocortisone resulted in full recovery in two cases of myocarditis in 12 year old patients 42 , and authors support that fatality is significantly reduced under opportune intervention during the first hours 42 . A more conservative attitude was adopted for the analyzed cohort from the Sri Lanka outbreak; with indications of strict bed rest, liquid maintenance, oxygen, close monitorization of vital signs and inotropic support when needed, and a clear avoidance of steroids and other empirical drugs 37 .
The importance of a rapid intervention (first hours) is exemplified by the case of a 25 year old Indian male, that presented with nonspecific abdominal epigastric pain and vomiting. Exams revealed myocarditis. The patient died in a few hours when he developed pharmacological and electrical refractory ventricular tachycardia while evaluating a much more invasive treatment option: the possibility of implanting a left ventricular assistance device. Positive DENV serology results were known later 34 . It is clear at this point, that therapy needs to be standardized for arbovirus-induced cardiomyopathy, comparing efficacy of treatments that have already been proposed, as well as new treatment options.

Discussion
The key for a successful outcome of CHIKV-induced cardiomyopathy is recognizing signs and symptoms early on. It is certainly a condition that can be life-threatening, which is why patients should be referred for cardiac assessment as early as possible, after displaying any of the previously mentioned symptoms. Identifying comorbidities is recommended as well to distinguish CHIKV-induced cardiomyopathy from an exacerbation of previous heart disease.
For dengue virus infection, it is now known that the cardiovascular involvement is mostly characterized by rhythm abnormalities (bradycardia), with no symptoms or complications. However, in moderate or severe cases where there was a cardiovascular affectation or complication, myocarditis has been an important issue. Myocarditis due to DENV infection may present several patterns such as "refractory shock", "heart failure", "arrhythmia", etc and It would be important to consider this diagnosis. In the case of CHIKV infection and cardiac involvement, myocarditis should be also considered.
Cardiac compromise is not so common in isolated episodes; but countries where chikungunya virus is an epidemic should be alarmed and well informed about this condition. Physicians should be encouraged to keep divulgating reports on the cardiovascular involvement of chikungunya virus disease, to raise awareness and ultimately encourage suitable diagnosis and intervention worldwide. Questions are still raised about the real incidence, as every outbreak seems to follow a different pattern, but what is needed the most is further investigation on therapy for this specific condition and in different age groups.
A significant issue arises with the diagnosis of myocarditis by arboviruses such as DENV and CHIKV, because a myocardial biopsy or cardiac magnetic resonance imaging needs to be considered and performed. However, performing these, in tropical areas where these arboviruses are prevalent, is very hard and there are many restrictions. The management of myocarditis, regardless its etiology, should be focused in the therapeutics oriented to the agent (virus, bacteria, etc); the cardiovascular events support (controllling heart failure, cardiogenic shock, arrhythmia, etc) and the treatment of the inflammatory process. The last one is under discussion and needs more research, although in some severe cases due to DENV, the corticosteroids administration changed the evolution given their positive benefits.
CHIKV would induce not just cardiovascular compromise and cardiovascular manifestations during the acute phase, but also at subacute and chronic stages 43-56. Today it is known that compromise during chronic disease is not just limited to the rheumatological manifestations. Nevertheless, in CHIKV, the definition of systemic manifestation or extra-articular compromise has not well defined. But in the case of atypical conditions, this was defined by PAHO/WHO during the expert consultation meeting in Managua, Nicaragua, 2016, and later published by WHO 43 .

Limitations
Limitations will always be the sporadic nature of these cases, something we need to be prepared for in future outbreaks. Methodologically, it should also be considered that the inclusion of reviews may cause a bias, but in some cases, some would serve to locate some additional key articles useful for a novel topic such as the one of this systematic review. Additionally, many studies did not report detailed information about laboratory diagnoses (Troponin, BNP, CK-MB, etc), imaging studies (echocardiography, magnetic resonance), final diagnoses (myocarditis, etc), as well management (inotropics, corticosteroids, etc) and outcomes (survival, death). Additionally, articles published in French have been excluded. This could be a limitation as the largest series of cases and their complications came from France in relation to the outbreak on La Reunion Island, and many of these were published in French. Nevertheless, from these publications we did not identify, initially by the title or the abstract, any relating to cardiovascular complications.

Conclusions
Finally, these observations on DENV and CHIKV associated cardiovascular manifestations could be useful for management of Zika virus infections, which are currently causing epidemics in Latin America 44-46 . Cardiovascular compromise has already been described and reported in fatal cases 47,48 . In addition, cardiovascular complications might be underdiagnosed in clinical practice 49 . Future research needs to focus on the potential cardiovascular complications of Zika virus infection, with prompt cardiovascular screening in suspected cases 45,49,50 . Other emerging arboviruses such as Mayaro 50-55 , Oropouche 52,53 , Venezuelan Equine Encephalitis 54,55 may be also causing cardiovascular compromise, or even be co-infecting.
We are still learning about the multiple clinical implications 56,57 of co-infection, including those affecting the cardiovascular system.
Author contributions AJRM and ERV formulated the research questions, designed the study, developed the preliminary search strategy, and drafted the manuscript. ABM and MFA refined the search strategy by conducting iterative database queries and incorporating novel search terms. MFA and ABM searched and collected the articles. All authors critically reviewed the manuscript for important intellectual content. All authors have read and approved the final version of the manuscript.

Competing interests
No competing interests were disclosed.

Grant information
The author(s) declared that no grants were involved in supporting this work.

Supplementary file 1: PRISMA checklist.
Click here to access the data.

Supplementary file 2: PRISMA flowchart showing the number of records identified, included and excluded.
Click here to access the data. General comment This is a very interesting article that compiles information relevant to an emerging and widely disseminated infection in the American continent whose complications are still under study and its impact still to be known. Specifically, there are some aspects of the review that need to be considered: Objectives: -Clearly specified focusing on the cardiovascular involvement of Chikungunya virus infection, frequency of presentation, clinical manifestations and laboratory elements such as the electrocardiogram Methodology -Articles published in French have been left out, which could be a limitation considering that the largest series of cases and their complications came from France in relation to the big outbreak on La Reunion island, and many of them published in French.

Open Peer Review
-The search criteria are wide: Chikungunya AND systemic manifestations, heart, cardiac. However, with these criteria, you could lose some reports of severe disease that do not appear under these search criteria. Chikungunya AND mortality or Death could be included. Also, more specific criteria could be used in order to answer the question the authors propose to find cardiovascular involvement in Chikungunya infection -The inclusion of dengue in the search and in the results escapes the objectives of this systematic review.
There is no reference to the use of PRISMA checklist in this review, if it was used, make it more explicit in each of the items.

Results
It is confusing and difficult to follow what results are obtained from the systematic review (40 articles) and what results are from articles not included in the review. The entire section of cardiovascular manifestations in dengue goes beyond the purpose of the study and should not be mentioned in the results. Comparisons with the cardiovascular compromise in chikungunya, which is appreciated, can be presented in the discussion. At the end of results and before management, the paragraph of studies determining the cardiovascular outcome in patients with chikungunya should be included in conclusions.

Discussion
It is not clear the meaning of the phrase cardiac compromise is not so common in isolated episodes. 1.
Thanks for your valuable comments. Certainly the topic of this systematic review (without meta-analysis), is on ongoing findings that in the near future will be better defined. Regard your assessment, unfortunately this arrived when two others reviews ago had been submitted; based on them, we have recently proceeded to develop the new revised version. Your comments are consistent with those from Dr. Vilcarromero in a significant magnitude. Then, most of your comments are addressed in the revised version of the paper, including clarification on the objectives as well on the Methodology (explaining more the search criteria as well the clarification regard the use of PRISMA checklist and flow diagram). Regard the language of articles included, we agree that this would be a limitation. Limitations are now better described in the new version of the article. As we explained, dengue cardiovascular compromise and manifestations was a necessary comparison for understanding of readers. In the manuscript entitled "Cardiovascular involvement and manifestations of systemic Chikungunya virus infection: A systematic review" authors have made a hard and interesting description of the cardiovascular effect by chikungunya virus infection. This analysis would be important to share with the scientific community; however it is necessary major changes in order to be ready for publication. Mainly, focus in the specific topic and put in order and properly the information in the paper.

General comments:
Objective: It s not clear, author start assessing that the objective focus among cardiovascular involvement and manifestation, however, other systemic manifestation or atypical manifestation also become relevant in the results section. Methodology The main objective of systematic reviews is to respond to a specific question. Initially authors seem to do that pointing on cardiovascular involvement, but then, when they write the introduction and results section, this main point seem to disappear or is not clear for the reader. However, in the discussion section, authors re-take the objectives again. Certainly, the big amount of information given in the introduction section and talking about the virus, history, classification, vector and cycles is very interesting, but it is not the purpose of this study. I suggest them shortening it and focussing on the cardiovascular involvement and complications. I also recommend displaying a flow (figure) of how papers were excluded and included. What guideline do the authors follow up in order to assess the risk of bias (PRISMA or Cochrane? It is possible you follow PRISMA approach (For example: ). Please give this information http://prisma-statement.org/PRISMAStatement/Checklist.aspx explaining the steps.
In the Methods section, the next key word "Chikungunya AND Systemic AND Manifestation" used 1,2 1 2 8.
cardiogénico shock, arrhythmia, etc) and the management of the inflammatory process. The last, is under discussion and needs more research, although in some severe cases by DENV, the corticosteroids administration changed the evolution. Discussion Authors say, "The key for a successful outcome of CHIKV-induced cardiomyopathy is recognizing signs and symptoms". Here I recommend repeating the most important ones.
Limitations This section would consider some of the bias common to this kind of study where there is no clinical trials included and where "case reports" were including. Bias such as "selection" or "publication" bias, etc.

Are the rationale for, and objectives of, the Systematic Review clearly stated? Partly
Are sufficient details of the methods and analysis provided to allow replication by others? Partly First, thanks for your initial comments on our systematic review (SR) (without meta-analysis). In second place we want to clarify that making for the first time a SR about cardiovascular involvement and manifestations of systemic Chikungunya virus infection implies comparisons with dengue, unavoidably, as well, to introduce readers about the systemic manifestations of chikungunya, to better understand the cardiovascular involvement and manifestations in this arboviral disease. By the way, still on this specific topic, many aspects will become more detailed along with research in the near future. In which our group is specifically also contributing with studies, already published on the cardiovascular electrocardiographical alterations, as well ongoing on the ecochardiographical and cardiovascular biochemical ones.

Is the statistical analysis and its interpretation appropriate?
Objective: It s not clear, author start assessing that the objective focus among cardiovascular involvement and manifestation, however, other systemic manifestation or atypical manifestation also become relevant in the results section. involvement and manifestation, however, other systemic manifestation or atypical manifestation also become relevant in the results section. Our SR has as objectives, not just one: -To systematically review published literature on the cardiovascular manifestations and involvement of systemic CHIKV infection; -To explore which are the main clinical cardiovascular features of chikungunya infection? -To identify which are the main electrocardiographical findings of chikungunya infection? All of them, are clearly developed in the section Synthesis of Results, which is the main part of the SR. Before that section, a brief introduction on other systemic manifestation or atypical manifestation of chikungunya infection is at Clinical Course, short section of just 3 paragraphs and atypical presentations, a section of just 2 paragraphs, which include, by the way, the transition to the cardiovascular aspects, developed in the section Synthesis of Results and later sections of the SR.

Methodology
The main objective of systematic reviews is to respond to a specific question. In our case, to three specific questions, with the proper context to make it readable and understandable given the novelty of the topic, as mentioned, also with ongoing research in multiple aspects.
Initially authors seem to do that pointing on cardiovascular involvement, but then, when they write the introduction and results section, this main point seem to disappear or is not clear for the reader. From the title it's clear that this SR is not only about the cardiovascular involvement, but also about cardiovascular manifestations of chikungunya. Nevertheless, we will make more clarifications on our Introduction regarding this.
However, in the discussion section, authors re-take the objectives again. Ok. Thanks.
Certainly, the big amount of information given in the introduction section and talking about the virus, history, classification, vector and cycles is very interesting, but it is not the purpose of this study. This is not properly a study, it is a SR, without meta-analysis. Then, we consider, given the still novelty of the topic, such aspects are necessary for the readers.

I suggest them shortening it and focussing on the cardiovascular involvement and complications.
We have done that at Synthesis of Results and later sections of the SR.

I also recommend displaying a flow (figure) of how papers were excluded and included.
With our submission we provided the PRISMA Flow Chart and Checklist. However, this was not published by the journal with our article. Considering its importance and agreeing with you about it, we will incorporate as a Figure 1 and including properly in the manuscript, and not as supplementary file of our submission.
What guideline do the authors follow up in order to assess the risk of bias (PRISMA or Cochrane? It is possible you follow PRISMA approach (For example: http://prisma-statement.org/PRISMAStatement/Checklist.aspx). Please give this information explaining the steps.
We followed the PRISMA statement, as recommended by F1000 Research. We will clarify more on We will consider the improvement of this Table. In Table 3, it is important to consider more information about the selected papers. I recommend a big table showing the different cardiovascular involvement/complication, for example: 1. the clinical diagnoses (heart failure, acute coronary syndrome, refractory shock, and rhythm abnormalities), relevant signs and symptoms, especially early signs/symptoms (chest pain, dyspnea, bradycardia, etc), laboratory diagnose (Troponin, BNP, CK-MB, etc), Imaging studies (echocardiography, Magnetic resonance), final diagnose (Myocarditis?), Management (inotropics, corticosteroid, etc) and outcome (survive, died). I consider, this data would be important to understand the impact of cardiovascular involvement due to CHIKV. Unfortunately the number of papers as well the data available is limited to fully performed that, although was discussed by the group of authors of this SR. Nevertheless, we will consider your comment to improve this Table. In dengue, now it is known that more about the cardiovascular involvement is mostly characterized by rhythm abnormalities (bradycardia) with no symptoms or complications. However, in moderate or severe cases where there was a cardiovascular affectation or complication, myocarditis has been an important cause. Myocarditis due to DENV infection may present several patterns such as "refractory shock", "heart failure", "arrhythmia", etc and It would be important to consider this diagnose. In the comparison with CHIKV infection and cardiac involvement, myocarditis, should be discussed. It is not clear what do authors try to assess when they say: "The cardiac tropism of CHIKV seem to be shared with DENV", it is important to clarify. Thanks for this comment. We will use it in the revised version.
Diagnose myocarditis by those arbovirus, need to consider a myocardial biopsy or a cardiac magnetic resonance, however performing these in tropical areas where these arbovirus are prevalent, is very hard. We fully agree with this.
The management of myocarditis, whatever is the etiology, focus in the management of the agent (virus, bacteria, etc); management of the cardiovascular event (heart failure, cardiogénico shock, arrhythmia, etc) and the management of the inflammatory process. The last, is under discussion and needs more research, although in some severe cases by DENV, the corticosteroids administration changed the evolution. We fully agree with this.