Ebook Prevention of cardiovascular diseases from current evidence to clinical practice: Part 2

(BQ) Part 2 book Prevention of cardiovascular diseases from current evidence to clinical practice presents the following contents: Chagas disease - A neglected disease; prevention and control of cardiovascular diseases - Policies, strategies and interventions; prevention and control of cardiovascular diseases focusing on low and middle ­income countries; posttraumatic stress disorder and cardiovascular disease,...

© Springer International Publishing Switzerland 2015

J.P Andrade et al (eds.), Prevention of Cardiovascular Diseases,

DOI 10.1007/978-3-319-22357-5_15

Disease

Marcia de Melo Barbosa , Maria do Carmo Pereira Nunes , and Regina Müller

Acute Rheumatic fever (ARF) and its chronic sequel, rheumatic heart disease (RHD) result from an autoimmune disease that starts with an infection caused by

Streptococcus pyogenes (Group A streptococci—GAS) and remain the most

com-mon cause of preventable childhood heart disease worldwide It follows a non- treated throat infection in susceptible children and teenagers (3- to 19-years old); and strongly relates to socioeconomic and environmental determinants, such as over-crowding, poor standard of living, poor access to medical care and inadequate expertise of health-care teams [ 1 2 ]

Epidemiology

Despite being considered today as “virtually eliminated” [ 3 ] after a documented decrease in the incidence of ARF in developed countries during the past 6 decades, RHD remains a medical and public health problem, especially in low and middle- income countries and in indigenous populations, where it causes disability and

M de Melo Barbosa , M.D., Ph.D ( * )

ECO Center , Hospital Socor , Belo Horizonte , Brazil

Interamerican Society of Cardiology

e-mail: marciambarbosa@terra.com.br

M do Carmo Pereira Nunes , M.D

School of Medicine, Federal University of Minas Gerais , Belo Horizonte , Brazil

premature death in children and young adults in their most productive years [ 1 ]

As stated recently, RHD does not get the same attention as cancer as a chronic communicable disease (NCD) “because it is a disease of the bottom billion of the poorest people in the world—one of the most neglected of the neglected diseases” [ 2 ]

In 2005, the World Health Organization (WHO) estimated a prevalence of at least

15.6 million cases of RHD worldwide, with 282,000 new cases (ARF) and 233,000 deaths related to RHD each year The burden of stroke due to RHD in less deve-

lo ped countries was also considered: 144,000–360,000 new strokes each year [ 4 ] However, these are conservative assumptions, and future incoming-data will show these fi gures to be dramatically underestimated [ 5 ]

In Brazil, estimates based on WHO epidemiological model and data from the last Census in 2010, appointed to around 30,000 new cases of ARF each year, of which around 12,800 can develop RHD [ 1 , 6 ] Brazilian offi cial fi gures have shown a sig-nifi cant reduction in the number of hospitalizations due to ARF and RHD in the last

10 years, however, in 2012, 2713 ARF and 4268 RHD hospital admissions were still reported [ 7 ], since, similar to other countries, Brazil has not yet implemented a national register system and a RHD control program Underreporting of cases and diffi culties in access to hospital admission, especially for adolescents and young adults, are very common

In a recent linkage study with 53,210 Brazilian in-hospital children and cents admitted for heart failure (HF) from 2001 to 2007 the survival analysis for the ARF/RHD patients showed only 61 %, 55 % and 36 % survival rate at 1, 2 and

adoles-7 years, respectively, with a hazard ratio observed for RHD patients’ death of 15.5 These poor results were strongly related to social conditions measured by human development index (HDI) of the patients’ residence [ 8 ]

Another Brazilian study with 100 RHD low-income patients in Sao Paulo ing the entire course of the disease concluded that costs of ARF/RHD amounted to approximately 1.3 % of the annual family income in this population Direct and indirect costs, such as school failure rate of 22 %, 23 % parents’ work absenteeism, about 5 % lost jobs, and the intangible costs associated with RHD, resulting from premature disability and death, and loss of intellectual opportunities, with its adverse effects on the socioeconomic family and society development The estimated annual cost of RF for society in Brazil was estimated in 2001 as US$ 51,144,347.00 [ 9 ] More recently, advocacy groups, including the World Heart Federation (WHF), have put greater efforts into rectifying this neglect disease [ 2 ] In April 2013, the WHF issued a statement of commitment to the strategic objective of a 25 % reduc-tion in premature deaths from ARF and RHD among individuals aged <25 years by the year 2025 To achieve the objective of controlling RHD and eliminating ARF,

analyz-fi ve strategic targets have been identianalyz-fi ed: (1) Comprehensive register-based control programs; (2) Global access to Benzathine penicillin G; (3) Identifi cation and devel-opment of public fi gures as “RHD champions”; (4) Expansion of RHD training hubs; and (5) Support for vaccine development [ 10 ]

A recent editorial about RHD discussed that the challenge regarding RHD does not relate to knowledge of the disease, but to the implementation of measures to control the disease globally [ 5 ], which depends on the political will of the govern-ments and inclusion of ARF in public health policies It requires advocacy, aware-ness, commitment, coordination, and resources [ 5 ]

M de Melo Barbosa et al.

Pathogenesis

The pathogenesis of ARF/RHD is complex and both environmental and genetic factors contribute to its etiology, but still remains incompletely understood [ 11 ]

Streptococcus , in the appropriate condition, triggers the pathogenic sequence that

starts with pharyngitis, leading, in a small percentage of cases (1 to 5 % of susceptible children), to ARF which, in about 60 % of the cases, will develop life- threatening valve lesions characteristic of RHD [ 2 ]

Several genes associated with RHD have been described, related to both the innate and adaptive immune responses The susceptibility of developing ARF/RHD

is associated with some alleles of HLA (human leukocytes antigens) class II genes (DRB1, DQB and DQA), as well as with TNF-α gene which are all located on human chromosome 6 HLA alleles are involved in antigen recognition by T lym-phocytes through the T cell receptor (TCR) TNF-α gene encodes the infl ammatory TNF alpha protein, which is involved in the infl ammatory process mediating heart- tissue lesions in RHD Several other associations have been established through single nucleotide polymorphisms (SNPs) for genes code for other proteins also involved with the immune response (innate and adaptive pathways) [ 11 ]

Molecular mimicry between streptococcal antigens and human proteins is tral to RHD pathogenesis, and mainly cardiac myosin epitopes and vimentin seem

cen-to be the major target antigens Aucen-toreactive T cells (CD4+) migrate from the peripheral blood to the heart and proliferate in the valves in response to stimulation with specifi c cytokines High TNF alpha, interferon gamma, and low IL4 are found

in the rheumatic valve IL-4+ cells are found in the myocardium; however, these cells are very scarce in the valve lesions of RHD patients IL-4 is a Th2-type cyto-kine and plays a regulatory role in the infl ammatory response mediated by Th1 cytokines These fi ndings indicate that the Th1/Th2 cytokine balance has a role in healing myocarditis, while the low numbers of IL-4-producing cells in the valves probably induce progressive and permanent valve damage [ 11 ]

Diagnosis

The diagnosis of ARF is essentially clinical and laboratory exams are not monic of the disease, only contributing to confi rm the infl ammatory process and the streptococcal infection Clinical diagnosis of carditis is usually made by the auscul-tation of a pathological mitral regurgitation (MR) murmur Jones criteria [ 12 ] cre-ated in 1944, are characterized in major and minor, and represent the gold standard for the diagnosis of the fi rst attack They are an epidemiological and not clinical tool

pathogno-for the initial attack and have been revised, modifi ed and updated by the American

For the initial attack, the presence of two major manifestations or of one major and two minor manifestations supported by the evidence of a preceding GAS infection indicates high probability of ARF For the diagnosis of recurrences in a

patient with established RHD, just two minor criteria plus evidence of preceding GAS infection is suffi cient The presence of chorea, insidious carditis and chronic valve lesions are exception and do not require any other criteria to be considered as having rheumatic fever [ 1 ]

Subclinical carditis (SCC) is also a major concern, since 16.8–27 % may have it

In endemic areas, strict adherence to the revised Jones criteria can result in agnosis of ARF [ 15 ] Failure to diagnose these patients can lead to severe adverse consequences since prophylaxis will not be started [ 16 , 17 ] In Australia, diagnosis rates increased signifi cantly when monoarthritis and SCC were included as major criteria and low-grade fever (≥37.5°) as a minor criterion [ 17 ]

The disease usually presents with an acute febrile onset, with variable nations of arthritis, carditis, chorea and skin manifestations Published criteria are useful for epidemiological purposes, but clinical judgment should prevail, espe-cially in areas of the world where RHD is still common

Table 1 Modifi ed Jones

criteria for the diagnosis of

rheumatic fever (1992)

Major criteria Minor criteria

Arthritis Arthralgia Chorea Elevation of infl ammatory markers

(ESR, CRP) Eritema marginatum Prolonged PR interval in the ECG Subcutaneous nodulous

Evidence of GAS infection

Adapted from Dajani et al., Jones criteria 1992 Update—AHA

ESR erythrocyte sedimentation rate, CRP C-reactive protein

Table 2 WHO Criteria (2004) for the diagnosis of the fi rst attack, recurrence and RHD (based on

the modifi ed Jones criteria )

First episode of ARF 2 major criteria or 1 major and 2 minor +

evidence of previous streptococcus infection

Recurrence of ARF in patients without established

RHD

2 major criteria or 1 major and 2 minor + evidence of previous streptococcus infection

Recurrence of ARF in patients with established

RHD

2 major criteria + evidence of previous streptococcus infection

Sydenham Chorea

Insidious rheumatic carditis

No other major criteria or evidence of previous streptococcus infection is required

Chronic valve lesions of the RHD: pure MS or MS

and MR diagnosis and/or aortic valve lesion with

characteristic rheumatic involvement

No additional criteria for the diagnosis

of RHD is necessary

Source : WHO 2004

M de Melo Barbosa et al.

Evidence of previous GAS infection is demonstrated by increased or rising streptolisin O titer or other antibodies or a positive throat swab for GAS Infl ammatory markers, such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are usually elevated Though unspecifi c, they can add in monitoring the infl amma-tory process and its remission

Major Clinical Manifestations

Arthritis

The classical presentation is that of migratory and asymmetric polyarthritis ing large joints, especially in the legs, and than migrating to other joints with some overlapping of joints involvement It occurs in approximately 75 % of the cases and should be differentiated from arthralgia (no infl ammatory signs) When associated with carditis, there seems to be an inverse correlation between the severity of the two fi ndings [ 1 ] It responds rapidly to anti-infl ammatories and thus, self- medication may mask the typical presentation

Carditis

It is the most serious manifestation of the disease, and the only one that leaves sequelae Clinically, it is present in 40–70 % of the cases, however the percentage is much higher when the diagnosis is made by echocardiography [ 18 , 19 ] Although there is a pancarditis (endocardial, myocardial and pericardial involvement), valve lesions are the ones responsible for the clinical presentation and prognosis Myocarditis can be diagnosed by histology, but it does not cause HF and systolic function is usually preserved at the initial presentation Pericardium involvement is not common, does not happen in isolation and does not lead to constriction, but the presence of a pericardial effusion may help confi rm the diagnosis [ 20 ]

The most common valve lesion is MR and its pan-systolic murmur does not indicate permanent lesion Aortic regurgitation (AR) is less common and stenotic lesions do not happen in the early stage of the disease Tricuspid regurgitation may occur in acute carditis secondary to pulmonary hypertension

The severity of carditis can vary from SCC to a fulminant form In SCC, vascular exam, X Ray and ECG are normal (except for a prolonged PR) Doppler echocardiogram is essential for its diagnosis, as it can detect pathological mild MR and/or AR [ 21 ] Mild carditis is present when there is tachycardia disproportional to the degree of fever, diminished S1 and MR systolic murmur Chest X Ray and ECG are normal (except for a prolonged PR), but Doppler echocardiogram shows mild or moderate regurgitations and a normal-sized left ventricle (LV) In the moderate

form, cardiovascular exam is abnormal, with signs of incipient HF, abnormal chest X Ray and ECG, and more severe regurgitations in the echocardiogram, with enlarged LV Finally, in the severe form, cardiovascular signs are more important, the patient presents in HF, with murmurs related to more severe degrees of regurgi-tation, arrhythmias, pericarditis, and several abnormalities on the ECG, chest X Ray and Doppler echocardiogram [ 20 ]

Chorea

Sydenham’s chorea may occur in association with other manifestations, but it may also be the sole expression It is a neurological disorder characterized by rapid and involuntary movements, which are more common during stress and cease during sleep Its incidence varies from 5 to 36 % and it occurs predominantly in female children and adolescents [ 20 ]

Eritema Marginatum

It is a rare skin manifestation (4–15 % of the patients), generally occurring at the beginning of the disease It is usually associated with carditis, but not with its sever-ity, being characterized by a non-itchy pink-red lesion, which predominantly affects the trunk and spares the face It may disappear within hours and it is diffi cult to detect in dark-skin patients [ 20 ]

Subcutaneous Nodules

They are fi rm and painless, varying greatly in size, and representing a rare tation (2–5 %) of the disease The overlying skin is not infl amed and they are usu-ally located over bones surfaces or tendons and best detected by palpation and not inspection Their presence is strongly associated with severe carditis [ 20 ]

Minor Manifestations

They are unspecifi c and only when associated with major criteria and evidence of previous GAS infection help to establish the diagnosis Fever and tachycardia out of proportion to the fever are usually present Fever is usually of low grade when there

is carditis without arthritis, and absent in isolated chorea [ 20 ]

M de Melo Barbosa et al.

After recovery from the initial episode, 72 % of patients will develop valve heart diseases [ 18 ] Recurrence of the disease can lead to progression of valve lesions with all its consequences, as HF, atrial fi brillation, stroke, infective endocarditis and pregnancy-related complications With progression of the disease, cardiac surgery becomes mandatory and, if not performed, premature death from RHD and its com-plications is frequent, with some countries presenting the unacceptable mean age of death <25 years [ 22 , 23 ] Otherwise, patients under regular secondary prophylaxis may present recovery on the severity of valve lesions

ECG

ECG is unspecifi c, since it can be normal in the presence of carditis A prolonged PR interval (minor sign) can be present in the absence of carditis Sinus tachycardia, ST-T abnormalities, low QRS and T amplitude in the frontal leads can be present [ 20 ]

Echocardiogram

Although echocardiogram has been shown to be much more sensitive in the diagnosis

of rheumatic lesions, screening by echocardiography is not always feasible, cially in low-income countries, where the disease is usually more prevalent Besides, physiological regurgitations in normal individual can be interpreted as secondary to RHD To avoid this misclassifi cation, regurgitation should be considered abnormal only in the presence of morphological valve abnormalities [ 21 ] (Table 3 )

Since secondary prevention can avoid adverse outcomes, early echocardiographic- based diagnosis of valve lesions by active surveillance strategies has been shown in several countries to be of major importance [ 24 – 27 ]

MR is the most frequent lesion in ARF, being present in up to 94 % of the cases Valve thickening and focal nodules in the distal portion of the leafl ets are frequent and disappear in the follow-up [ 28 ] AR is not a frequent lesion in ARF, but in males

it can occasionally be an isolated lesion Stenosis is a late fi nding LV dilation may

be present and both cardiomegaly and valve regurgitation can disappear Systolic function is usually preserved and HF, when present, is considered nowadays to occur due to valve lesion and not to myocardium involvement

In patients with chronic RHD, recurrence is always associated with carditis, which can be expressed as pericarditis, new or worsening of a pre-existing valve regurgitation, increase in cardiac silhouette and HF Size and function of cardiac chambers, left valve abnormalities (stenosis and regurgitation), tricuspid lesion (much less frequent) and associated pulmonary hypertension can all be adequately detected by echocardiography in RHD

rheumatic heart disease a All four Doppler echocardiographic criteria must be met

M de Melo Barbosa et al.

Treatment

General Measures

Treatment aims to suppress the acute infl ammatory process, minimizing clinical repercussions on the heart, joints and central nervous system, in addition to eradi-cating GAS infection and promoting relief of main symptoms [ 20 , 29 ]

Absolute bed rest is no longer recommended, except in the presence of carditis, when bed rest, at least during the symptomatic stage, is recommended Return to normal activities should be gradual depending on the improvement of symptoms and normalization or marked reduction of infl ammatory activity tests

In cases of high temperature, paracetamol is recommended as a fi rst option, and dipyrone as a second Anti-infl ammatory drugs, including acid acetylsalicylic, are not indicated before the diagnosis of ARF is confi rmed [ 20 ]

Anti-infl ammatory and Corticosteroids

The fi rst lines of symptomatic therapy are anti-infl ammatory agents, ranging from salicylates to steroids [ 27 , 30 , 31 ] Salicylates markedly reduce fever and relieve joint pain and swelling, but they have no effect on the natural course of the disease Adults may require large doses of aspirin, 0.6–0.9 g every 4 h, while children are treated with lower doses Corticosteroids are not frequently used because they offer no therapeutic benefi ts and may mask the presence of other illnesses causing arthritis [ 20 , 29 ]

Therapeutic Modalities

Acute carditis has generally been treated with steroids even though they have

no effect on the progression of RHD Nevertheless, in the setting of severe, tially life-threatening HF, steroid administration is largely employed [ 20 , 29 – 31 ] Treatment of cardiac manifestations follows established guidelines, including man-agement of HF and severe valve regurgitation Digitalis can be used but with special attention because of the risk of development of heart block Cardiac surgery should

poten-be avoided whenever possible during ARF, poten-being indicated only in the presence of severe valve regurgitation with HF refractory to drug therapy [ 20 , 29 , 31 ]

Treatment for chorea is indicated only in severe forms, when uncoordinated movements interfere with usual activity of the patients Drugs used to control cho-rea symptoms are haloperidol, valproic acid, and carbamazepine Small series have studied corticosteroids, along with plasmapheresis and intravenous immunoglobulin,

to assess their infl uence on the severity and time course of symptoms, but there is not enough evidence for the indication of these therapies [ 20 , 29 ]

strepto-9 days after the onset of the infection [ 20 , 29 ] Early treatment of streptococcal pharyngitis is especially recommended in countries with a high prevalence of ARF

to avoid the development of new cases of the disease, since the transmission rate in untreated patients is approximately 35 % in close contacts (families, schools, or other agglomerations) It is noteworthy that 24 h after beginning treatment with penicillin, patient becomes minimally contagious [ 20 ]

Intramuscular Benzathine penicillin G and oral V penicillin are the recommended for the treatment of streptococcal pharyngitis, except in individuals with history of penicillin allergy (Table 4) Benzathine penicillin remains the drug of choice because it is cost-effective, has a narrow spectrum of activity, long-standing proven effi cacy, low incidence of side effects, and good adherence to the regimen imposed Furthermore, to date, penicillin-resistant GAS has not been registered

The oral antibiotics of choice are V penicillin and amoxicillin (Table 4 ) All patients should continue to take penicillin regularly for an entire 10-day period, even though they likely become asymptomatic after the fi rst few days Oral cepha-losporin, indicated for penicillin-allergic patients, have been used in shorter than 10-day courses, with high compliance, bacterial elimination and clinical response that may be superior to penicillin treatment However, evidence is insuffi cient to recommend this treatment regimen in endemic areas Azithromycin can be used in shorter treatment regimen (3–5 days) [ 20 , 29 ], however, proven resistance to GAS has been reported Aggressive antibiotic therapy for primary prevention is essential

in areas where RF is prevalent and may represent the best hope for decreasing the overall health care burden of RHD [ 32 ] In contrast, in populations where ARF is rare, antibiotic use results in modest therapeutic benefi t, and the risk-benefi t ratio has been called into question

Certain antimicrobials are not recommended for treatment of GAS upper respi ratory tract infections [ 29 ] Tetracyclines should not be used because of the high prevalence of resistant strains Sulfonamides and trimethoprim-sulfa-methoxazole do not eradicate GAS in patients with pharyngitis Older fl uoroqui-nolones (eg, ciprofl oxacin) have limited activity against GAS and newer

fl uoroquinolones (eg, levofl oxacin, moxifl oxacin) are active in vitro against GAS but are expensive and have an unnecessarily broad spectrum of activity, and therefore, they are not recommended for routine treatment of streptococcal phar-yngitis [ 29 ]

M de Melo Barbosa et al.

Secondary Prevention

Prevention of recurrent episodes of GAS pharyngitis is the most effective method to prevent the development of severe RHD [ 20 , 29 ] Recurrences of ARF are most common in patients who have had carditis during their initial episode A recurrent attack can be associated with worsening of the severity of RHD that developed after

a fi rst attack, or less frequently with the new onset of RHD in individuals who did not develop cardiac manifestations during the fi rst attack

For these reasons, prevention of recurrent ARF requires continuous antimicrobial prophylaxis The preferred method of prophylaxis is with Benzathine penicillin G, 1.2 million units intramuscularly every 3 weeks (Table 5 ) [ 20 , 30 ]

Successful oral prophylaxis depends primarily on patient adherence to prescribed regimens The recommended oral agent is V penicillin The dosage for children and adults is 250 mg twice daily (Table 5 ) There are no published data about the use of other penicillins, macrolides, azalides, or cephalosporins for the secondary preven-tion of rheumatic fever If the patient is allergic to penicillin, sulfadiazine is recom-mended Although sulfonamides are not effective in the eradication of GAS, they prevent infection For the patient who is allergic to both penicillin and sulfadiazine,

an oral macrolide (erythromycin or clarithromycin) [ 20 , 29 ]

Recurrences are uncommon after 5 years following the fi rst episode and in patients over 25 years of age Prophylaxis is usually discontinued after these times, except in groups with a high risk of streptococcal infection, such as parents or teach-ers of young children, nurses, military recruits, etc

Secondary prevention of RF depends on whether carditis has occurred (Table 6 )

If there is no evidence of carditis, preventive therapy can be stopped at age 21

If carditis has occurred but there is no residual valve disease, it can be stopped at

10 years after the fi rst episode If carditis has occurred with residual valve involvement,

it should be continued for 10 years after the last episode or until the age of 40 years,

if the patient is in a situation in which re-exposure would be expected [ 29 ] Lifelong prophylaxis should be considered in high-risk patients according to the severity of valve heart disease and exposure to group A streptococcus, in a situation in which

Table 5 Secondary prevention of rheumatic fever

Benzathine penicillin G <20 kg: 600,000 U IM Every 3 weeks

≥20 kg: 1,200,000 U IM

Penicillin allergic

Penicillin and sulfadiazine allergic

Sources : Arq Bras Cardiol.2009;93 (3 supl.4):1–18

Circulation 2009 24; 119(11):1541–51

M de Melo Barbosa et al.

reexposure would be expected The decision to discontinue prophylaxis should be made after discussion with the patient of the potential risks and benefi ts, consider-ing the epidemiological risk factors.

In summary, RHD remains a major public health problem in many countries throughout the world, with the unfair profi le of affecting children and young adults

of poor and developing countries, with devastating personal and economical burden for this already sacrifi ced population Low- or middle-income countries still do not have coordinated, national control programs [ 5 ] A remarkable transformation lead-ing to increased advocacy for the establishment of comprehensive approaches to RF/RHD control, encompassing primary and secondary prevention, treatment of established RHD, broad education and health promotion strategies, is highly neces-sary [ 32 ] RF vaccine is still a future possibility [ 5 ], but its development will bring new hope to this diffi cult scenario [ 20 ]

References

1 World Health Organization Rheumatic fever and rheumatic heart disease: report of a WHO expert consultation on rheumatic fever and rheumatic heart disease World Heart Organization Geneva, 2001 October 29–November 1 Geneva: WHO 2004

2 Maurice J Rheumatic heart disease back in the limelight Lancet 2013;382:1085–6

3 Braunwald, E Introduction to heart failure compendium In: Research advances in heart failure:

a compendium Circul Res, published online July 25, 2013 doi: 10.1161/CIRCRESAHA 113.3022541

4 Carapetis JR, Steer AC, Mulholland EK, Weber M The global burden of group A streptococcal disease Lancet Infect Dis 2005;5:685–94

5 Carapetis JR, Zühlke L, Taubert K, Narula J Continued challenge of rheumatic heart disease: the gap of understanding or the gap of implementation? Glob Heart 2013;8(3):185–6

6 Müller RE Cardiopatia reumática com lesão valvar em crianças e adolescentes: fatores ciados ao tempo até a terapêutica cirúrgica [Tese de Doutorado] Rio de Janeiro: Doutorado

asso-em Saúde da Criança e da Mulher, Instituto Fernandes Figueira, Fundação Oswaldo Cruz;

2011 [Thesis in Portuguese]

7 DATASUS Ministério da Saúde - Sistema de Informações Hospitalares do SUS (SIH/SUS) Disponível em http://www.datasus.gov.br/ Acesso em 27/10/2013 [Data in Portuguese]

Table 6 Duration of secondary rheumatic fever prophylaxis

Category Duration after last attack

Rheumatic fever with carditis and

residual heart disease a

10 years or until 40 years of age (whichever is longer), sometimes lifelong prophylaxis

Rheumatic fever with carditis, but

no residual heart disease

10 years or until 21 years of age (whichever is longer)

Rheumatic fever without carditis 5 years or until 21 years of age (whichever is longer)

Sources : Arq Bras Cardiol.2009;93 (3 supl.4):1–18

Circulation 2009 24; 119(11):1541–51

a Patients at high risk for repeated episodes of rheumatic fever, such as those at signifi cant risk of recurrent exposure to group A streptococcus infection, should be considered for life-long antibiotic prophylaxis

8 Azevedo VMP, Kaufman R, Chaves RBM, Santos MA, Kuschnir MCC, Santos B, Santos AMR, Xavier RMA Survival analysis in the real world of 53,210 children and adolescents hospitalized for heart failure between 2001 and 2007 in a developing country using probabilis- tic linkage of databases Circulation 2012;125(19):e33–4

9 Terreri MT, Ferraz MB, Goldenberg J, Len C, Hilário MO Resource utilization and cost of rheumatic fever J Rheumatol 2001;28(6):1394–7

10 Remenyi B, Carapetis J, Wyber R, Taubert K, Mayosi BM Position statement of the World Heart Federation on the prevention and control of rheumatic heart disease Nat Rev Cardiol 2013;10:284–92

11 Guilherme L, Köhler K, Kalil J Rheumatic Heart Disease: mediation by complex immune events Adv Clin Chem 2011;53:31–50

12 Jones TD The diagnosis of rheumatic fever JAMA 1944;126:481–4

13 Dajani AS, Ayoub E, Bierman FZ Guidelines for diagnosis of rheumatic fever: Jones criteria,

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14 Ferrieri P, Baddour L, Bolger A, Dajani A, Pallasch T, Tani L, et al Proceedings of Jones Criteria Workshop (AHA Scientifi c Statement) Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in the Young of the American Heart Association Circulation 2002;106:2521–3

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16 Tubridy-Clark M, Carapetis JR Subclinical carditis in rheumatic fever: a systematic review Int J Cardiol 2007;119:54–8

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20 Barbosa PJB, Müller RE, Latado AL, Achutti AC, Ramos AIO, Weksler C, et al Diretrizes Brasileiras para Diagnóstico, Tratamento e Prevenção da Febre Reumática da Sociedade Brasileira de Cardiologia, da Sociedade Brasileira de Pediatria e da Sociedade Brasileira de Reumatologia Arq Bras Cardiol 2009;93 (3 supl.4):1–18 [Article in Portuguese]

21 Remenyi B, Wilson N, Steer A, Ferreira B, Kado J, Kumar K, et al World Heart Federation criteria for echocardiographic diagnosis of rheumatic heart disease—an evidence-based guide- line Nat Rev Cardiol 2012;9:297–309

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23 Kumar R, Raizada A, Aggarwal AK, Ganguly NK A community-based rheumatic fever/ rheumatic heart disease cohort: twelve-year experience Indian Heart J 2002;54:54–8

24 Marijon E, Ou P, Celermajer DS, Ferreira B, Mocumbi AO, Jani D, Paquet C, Jacob S, Sidi D, Xavier J Prevalence of rheumatic heart disease detected by echocardiographic screening N Engl J Med 2007;357:470–6

25 Carapetis JR, Hardy M, Fakakovikaetau T, et al Evaluation a screening protocol using tation and portable echocadiography to detect asymptomatic rheumatic heart disease in Tongan schoolchildren Nat Clin Pract Cardiovasc Med 2008;5:411–7

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27 Marijon E, Mirabel M, Celermajer DS, Jouven X Rheumatic heart disease Lancet 2012; 379:953–64

28 Vasan R, Shirivastava S, Vijayakumar M, Narang N, Lister B, Narula J Echocardiographic evaluation of patients with acute rheumatic fever and rheumatic carditis Circulation 1996; 94:73–82

29 Gerber MA, Baltimore RS, Eaton CB, Gewitz M, Rowley AH, Shulman ST, Taubert

KA Prevention of rheumatic fever and diagnosis and treatment of acute Streptococcal

pharyn-M de Melo Barbosa et al.

gitis: a scientifi c statement from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee of the Council on Cardiovascular Disease in the Young, the Interdisciplinary Council on Functional Genomics and Translational Biology, and the Interdisciplinary Council on Quality of Care and Outcomes Research: endorsed by the American Academy of Pediatrics Circulation 2009;119(11):1541–51

30 Raju BS, Turi ZG Rheumatic fever In: Bonow RO, Mann DL, Zippes DP, Libby P, editors Braunwald’s heart disease: a textbook of cardiovascular medicine 9th ed Philadelphia: Elsevier-Saunders; 2012 p 1869–74

31 Bonow RO, Carabello BA, Chatterjee K, de Leon Jr AC, Faxon DP, Freed MD, Gaasch WH, Lytle BW, Nishimura RA, O’Gara PT, O’Rourke RA, Otto CM, Shah PM, Shanewise JS, 2006 Writing Committee Members, American College of Cardiology/American Heart Association Task Force 2008 Focused update incorporated into the ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College

of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease): endorsed by the Society of Cardiovascular Anesthesiologists, Society for Cardio- vascular Angiography and Interventions, and Society of Thoracic Surgeons Circulation 2008;118(15):e523–661

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© Springer International Publishing Switzerland 2015

J.P Andrade et al (eds.), Prevention of Cardiovascular Diseases,

DOI 10.1007/978-3-319-22357-5_16

Chagas Disease: A Neglected Disease

José Antonio Marin-Neto , Anis Rassi Jr , Andréa Silvestre de Sousa ,

João Carlos Pinto Dias , and Anis Rassi

Introduction

In 1909, the Brazilian physician Carlos Chagas reported to the scientifi c community

the discovery of a new pathogenic agent, Trypanosoma cruzi ( T cruz i) and the

pre-viously unknown illness it caused [ 1 ] Far from being rare, it was soon noted that the new disease affected millions of people across nearly the entire Latin American subcontinent The recovery of T cruzi genetic material from South American

J A Marin-Neto , M.D., Ph.D ( * )

Cardiology and Pneumology from the University of Sao Paulo , Sao Paulo , Brazil

Interventional Cardiology from the Hospital das Clinicas , Ribeirão Preto Medical School , Sao Paulo , Brazil

Federal University of Rio de Janeiro , Rio de Janeiro , Brazil

Oswaldo Cruz Foundation , Rio de Janeiro , Brazil

e-mail: andrea.silvestre@globo.com

J C P Dias , M.D., Ph.D

School of Medicine , Federal University of Minas Gerais , Belo Horizonte , Brazil

Neglected Diseases Committee of the World Health Organization , Genève , Switzerland

e-mail: jcpdias@cpqrr.fi ocruz.br

A Rassi , M.D

Faculty of Medicine , Federal University of Goias , Goiania , Goias , Brazil

mummies in paleoparasitological studies provided evidence that Chagas disease had already affected human beings at least 9000 years ago [ 2 ]

A few years later, Carlos Chagas and a group of collaborators—Belisário Penna, Eurico Villela, and Ezequiel Dias, among others—succeeded in characterizing the main clinical manifestations of the disease in the cardiovascular system [ 3 ] The chief mode of disease transmission between humans, involving hematophagous

mosquitos of the family Triatominae , was described soon afterwards

Despite the unassailable success and distinction of the aforementioned research,

Chagas disease endured periods of complete oblivion during the twentieth century,

in the words of pathologist Fritz Köberle, in addition to an early continuous relative neglect by a segment of the medical and scientifi c communities As a result, undeni-able gaps remain in the elucidation of the pathogenesis of the cardiovascular involvement, as well as some uncertainty regarding the clinical management of the disease

In the present chapter, aspects that remain unclear relative to the pathogenesis of Chagas heart disease (CHD) and its overlooked prevention at the primary, second-ary and tertiary levels are reviewed

of the cardiac intramural ganglia, particularly those of the parasympathetic subtype, with consequent dysregulation of autonomic circulatory control The cardiac dysau-tonomia observed in patients with CHD results in abolition of the overall vagal inhibition of the sinoatrial node and also deprives such patients of the mechanism of rapid adjustment of the heart rate to transient variations of the systemic arterial pres-sure and venous return Based on those changes in the intrinsic cardiac nervous system, characterized by the (non-exclusive) predominance of parasympathetic denervation, the so-called neurogenic theory of CHD postulated that autonomic imbalance accounted for a true heart disease induced by excessive adrenergic stimu-lation [ 5 ] However, this theory could not be validated due to the lack of correlation between the degree of parasympathetic denervation and the extent of myocardial injury, among other factors [ 4 ] Nevertheless, the hypothesis that cardiac dysauto-nomia may contribute to the occurrence of malignant arrhythmias and sudden death

as well as to the development of disorders of coronary microcirculation regulation, remains attractive [ 4 ]

Indeed, various microcirculatory abnormalities were described in experimental

models of T cruzi infection and in human individuals with CHD, including

throm-bosis, spasm and endothelial dysfunction associated with amplifi ed platelet activity [ 6 ] Such disorders might be due to the tissue infl ammatory changes induced by

infection with T cruzi , or to the immune reactions consequent to infection Together,

these microcirculatory abnormalities might cause ischemic myocardial injury and superimposed fi brosis [ 7 ] These disorders might play a role in the genesis of symp-toms, such as atypical angina, which is common among individuals with CHD, and might cause the myocardial perfusion defects that are frequently observed Although the coronary arteries of CHD patients are normal on angiography, abnormal responses to vasodilator and vasoconstrictor stimuli at subepicardial levels have also been reported The hypothesis that microcirculatory abnormalities participate in the formation of the characteristic fi brotic and aneurysmal lesions found in most patients with CHD, particularly in the apical and inferoposterior regions of the left ventricle, namely, vascular areas of relative separation among the various territories of coro-

nary distribution ( watershed ) is quite plausible [ 8 ] Chest pain is possibly the most neglected among the symptoms commonly exhibited by CHD patients, and its clini-cal treatment only recently became the specifi c target of a study still in progress [ 9 ] Several convincing clues suggest that autoimmune mechanisms participate in the pathogenesis of CHD, as cardiac injury was found to occur after immunization with

T cruzi antigens and the passive transfer of lymphocytes from infected animals,

whereas chronic myocarditis was attenuated once the animals became tolerant to myocardial antigens [ 10 ] The immune response to parasitic infection, involving polyclonal activation or molecular mimicry, might itself represent a mechanism of aggression to the myocardium [ 11 ]

Nevertheless, the actual role of autoimmunity in the pathogenesis of the lesions characteristic of the chronic stage of disease is rather poorly established Yet, the hypothesis that the nature and intensity of the host’s immune response to the pres-ence of parasites in the tissues might behave as a true “doubled-edged sword” remains plausible When the immune system is depressed by disease (e.g., by coin-fection with the human immunodefi ciency virus—HIV) or iatrogenically (e.g., in

transplanted patients to avoid rejection), infection with T cruzi is patently

exacer-bated This fact indicates that before being suppressed, the immune system seeks to prevent infection with the parasite, and thus it is an inherently protective factor In accord with that theory, a persistently well-modulated immune response might rep-

resent the primary mechanism by which most patients with chronic T cruzi

infec-tion remain with the indeterminate form of Chagas disease for life (i.e., without clinical manifestations of heart disease or gastrointestinal disorders—“megas”) The impression resulting from the aforementioned considerations on ambivalent (benefi cial or harmful) immune mechanisms in CHD notwithstanding, a growing consensus holds that the persistence of the parasite in the tissues is the fundamental pathogenic factor in the myocardial affl iction characteristic of the chronic disease stage [ 4 , 12 – 14 ] The evidence supporting that consensus derive from multiple sources, including both experimental research and human studies as discussed

Chagas Disease: A Neglected Disease

below, together with the all-important issue regarding the prevention of CHD

devel-opment in patients with chronic T cruzi infection

To summarize, several crucial aspects of the etiopathogenesis of CHD have not yet been defi nitively elucidated [ 15 ] Whereas the available pathogenetic hypothe-ses and theories are reasonable to some extent, they lack fi rm support in conclusive studies Thus, in the course of one century of research, some negligence in the approach to CHD pathogenesis appears to have been unavoidable Such relative negligence appears obvious, for example, in the fact that over one decade, some studies and investigators insisted repeatedly in asserting certain aspects of the pathophysiology of CHD instead of seeking to investigate more objectively and persistently the consequences of those disorders to elucidate the prognostic mean-ing of the abnormalities that were already exhaustively demonstrated [ 16 ]

Prevention of CHD

Vector-borne transmission remains the main route of human infection with T cruzi

and is usually associated with the vector’s blood meals Indeed, the hematophagous insects defecate while sucking the host’s blood, and thus the parasites enter the bloodstream through the skin disruption caused by the sting, or even through intact mucous membranes close to the sting site The insects also played a role, albeit passive, in recently reported outbreaks of infection via the intake of contaminated food, that is, during the preparation of food (usually during the grinding of sugar-cane, açaí palm, etc.) [ 17 , 18 ] As a result of the interventions that led to the eradica-tion of the main vectors in Latin America, the oral route of transmission became the most common route in several countries, including Brazil The second most fre-

quent route of transmission of infection with T cruzi is via blood transfusions, the

prevalence of which is most likely underestimated due to poor reporting within the medical sector [ 19 ] This is the most pertinent route of transmission of infection in countries where Chagas disease is not endemic, due to the lack of effi cacious sero-logic control and the increasing number of infected immigrants from Latin America, particularly in Europe and the United States

The incidence of vertical mother-to-child transmission of infection through the transplacental route is estimated to vary from 1 % in Brazil to 7 % in some areas of Bolivia and Paraguay, depending on factors such as parasite strain, the mother’s immune status and the diagnostic technique used to detect infection [ 20 ] Transmission

is less often due to transplantation of organs donated by infected individuals or to laboratory accidents Most of the cases of transmission via transplanted organs occur

in countries where Chagas disease is not endemic and are due to the lack of effi cious and validated serologic techniques, lack of familiarity with the manifestations

ca-of acute disease and the presence ca-of Latin American donors, many ca-of whom have dual citizenship, which may make the identifi cation of high-risk donors diffi cult Among the parasitic diseases, only malaria and schistosomiasis are more signifi -cant from an epidemiological point of view than Chagas disease [ 21 ] Chagas disease was historically confi ned to rural areas with very low levels of social develop-

ment in nearly all of the continental Latin American countries That scenario changed quite recently, as the epidemiological signifi cance of Chagas disease in those coun-tries was greatly reduced [ 22 ] In global terms, 8–10 million people are currently estimated to be infected [ 23 , 24 ] versus 16–18 million in the 1990s [ 25 ] In parallel,

as a function of migration circuits involving infected individuals from endemic tries, Chagas disease became a public health problem in the United States and other countries, such as Spain, Belgium, France, England, Japan and Australia [ 26 ] Such epidemiological transitions in non-endemic countries accentuated the concern regarding the possible transmission of infection via blood transfusions, solid organ donation and the transplacental route Additionally, the search for diagnostic and clinical treatment methods for infected individuals was intensifi ed in those countries, which also targeted the prevention of transmission to other people [ 27 ]

The methods available to reduce the medical and social impact of Chagas disease are based on three levels of prevention, primary, secondary and tertiary, and are discussed next [ 28 ] (Fig 1 )

Primary prevention seeks to avoid the occurrence of new infections, i.e., to nate the risk of infection of exposed individuals and to interrupt the chain of transmission Those goals are mainly achieved by means of strategies focusing on the control of both vector- and non-vector-borne transmission However, in the case

elimi-of the vertical route, it should be borne in mind that there is no procedure available

to reliably impede mother-to-child transmission

Secondary prevention consists of the screening and detection of individuals

infected with T cruzi in the early stages of disease This strategy is essential in acute

cases In chronic cases, and more particularly those with the indeterminate form of

Prevention level Primary prevention Secondary prevention

Target population Individuals Early/asymptomatic

• Vector control • Screening

• Prevention of • Detection of infected

of transmission individuals Strategies

via blood transfusions • Early intervention

• Prevention of • Antiparasitic transmission treatment via organ transplantation • Periodic health exams

• Care in laboratory

handling ofT cruzi

• Public health • Primary care Responsible entities • Primary care • Public health

• Other Intervention • Prevent transmission • Avoid progression of

to the clinical forms

of disease

Indeterminate form

Tertiary prevention

Established disease

• Antiparasitic disease (selected cases)

• Pharmacological and non-pharmacological interventions

• Symptomatic treatment

• Management of complications

Cardiac and digestive forms

Disease progression

Chagas disease absent

of Chagas disease

Fig 1 Strategies for prevention of Chagas disease [ 28 ]

Chagas Disease: A Neglected Disease

Chagas disease, particularly asymptomatic individuals who are often unaware of being infected, the aim of secondary prevention is to provide etiological treatment Eradication or reduction of the parasite load may in principle avoid or delay the progression of disease into the determinate chronic forms and contributes to inter-rupting the infection’s epidemiological chain of transmission

Tertiary prevention consists of the clinical interventions performed to limit the morbidity and mortality of established disease in a special manner as concerns CHD

Primary Prevention of Chagas Disease

Since the era of Carlos Chagas and colleagues, the belief has been held that the control of infection could be more easily attained by means of primary prevention Currently, primary prevention is still centered on the control of vectors by chemical means, in addition to the screening of blood donors using sensitive and specifi c serologic methods Such measures must be continuously supported by strategies targeting basic health education, effective participation of the community in pro-grams, improvement of housing conditions and constant epidemiological surveillance The reward for such strategies is immediate when they are rigorously implemented, as the number of new vector-borne infections is reduced The rate of infection through blood transfusions decreases soon afterwards In areas where vector-borne and blood transfusion transmission are controlled, the number of infected pregnant women is progressively reduced, whereby vertical transmission exhibits a signifi cant tendency towards reduction The early detection of infection in fetuses allows for specifi c treatment of the affected children [ 29 , 30 ] Moreover,

primary prevention strategies targeting care in the laboratory handling of T cruzi are

quite effective by avoiding work accidents Similarly effective is the adequate screening of organ donors through the application of universal serologic techniques

in locations where the seroprevalence is high, or also the use of serologic tests bined with specifi c epidemiological investigation

Alternatively, the opportunities to diagnose infection with T cruzi and to provide

etiological treatment before women become pregnant to prevent vertical sion are rare Additionally, the prevention of infection by the oral route is practically impossible Therefore, in both instances, the most effective strategy to control infection consists of early detection and trypanosomicidal treatment

Preventive immunization by means of a safe and effective vaccine is not yet available, partially as a function of the theoretical risk of adverse immune reactions [ 31 ] Another hindrance is represented by the multiple molecular variants of T cruzi

[ 32 ], which confounds the search for an adequate vaccine by a rather indefi nite antigenic target [ 33 ]

The implementation of control programs depends on three essential factors: acknowledgment of the medical signifi cance of the disease; defi nition of its social impact; and the availability of resources and minimal strategies aimed at control Following the most characteristic period of oblivion to Chagas disease, the modern

era of combat against the disease began between 1945 and 1955, when residual insecticides were used to combat the vectors and pathologic, serologic and clinical studies became systematized [ 34 ] Beginning in the 1960s, national programs of

vector control were launched; serologic screening for T cruzi in blood banks became

mandatory in the 1980s, parallel to the measures established for the control of the emerging HIV pandemic [ 19 , 34 ]

Control of Vectors

Vector control is essential under conditions of domiciliary and peridomiciliary infestation, by means of continuous and regular application of residual insecticides also followed, in principle, by continuous and sustained epidemiological surveil-lance Synthetic pyrethroids derived from chrysanthemic acid (deltamethrin, lambda-cyhalothrin, cyfl uthrin, etc.) are currently the most effective insecticides In cases of resistance to those agents, which seldom occurs, organochlorine or carba-mate compounds may be alternatively used [ 34 ]

The perception that population-based educational campaigns and active participation of the community in strategies for vector control are an essential part

of epidemiological surveillance is universally accepted Improvement of housing conditions is also quite effective; however, except for rare exceptions (such as the

2001 experience in Venezuela), this has never been properly prioritized in national programs [ 35 ]

It should be noted that eradication, namely, complete interruption of Chagas ease transmission, is practically an unattainable epidemiological target Even in places where that goal could be partially achieved, such as the extinction of trans-

dis-mission by Triatoma infestans in countries such as Uruguay, Chile and Brazil,

entomological surveillance must be maintained for many years The proposal that

infection with T cruzi evolved from a primitive type of zoonosis to a true and highly

spread anthropozoonosis is currently very clear Moreover, the parasite is currently disseminated across many sylvatic areas, in which its ecotopes are being increas-ingly altered by human activity (e.g., indiscriminate deforestation) such as in the Amazon region, where the incidence of autochthonous cases is increasing [ 36 ] Evidence also exists for the presence of several secondary vectors, namely, triato-mine insects potentially susceptible to domiciliation, as well as that of vector resistance to the most commonly used insecticides

Control of Transmission via Transfusions

Although less rigorous, this strategy was applied as early as the 1990s, through the serologic detection and chemoprophylaxis of suspected blood, and intensifi ed in par-allel with the establishment of measures against infection with HIV Ideally, two

Chagas Disease: A Neglected Disease

highly accurate serologic tests based on two different techniques (e.g., indirect nofl uorescence and ELISA) should be employed for the screening of blood donors However, starting in 2002, the World Health Organization (WHO) recommends

performing only one test (ELISA) to detect blood donors infected with T cruzi [ 20 ] Likely due to technical inadequacies in the performance of the serologic tests, this recommendation led to a signifi cant reduction in the sensitivity of detecting infected blood and organ donors, the consequences of which are only beginning to be under-stood For example, acute Chagas infection was detected in one individual without Chagas disease who received the transplanted liver of an allegedly non-infected donor

in Brazil, which is an endemic country [ 37 ] The challenge is heightened by the fact that a large fraction of the donors and recipients are transfused with large amounts of blood components on the occasion of the event leading to death or in the perioperative period of heart transplantation, respectively Under such circumstances, high-sensitiv-ity serologic control of hemodiluted sera, with suffi cient specifi city so as not to reject viable organs should be mandatory The need to improve the methods for serologic

detection of T cruzi infection in endemic and non-endemic areas is reinforced by the

recent description of a series of patients with chest pain and segmental wall-motion abnormalities of the left ventricle (such as apical aneurysm) highly suggestive of CHD, but who had negative results by the immunofl uorescence serologic test [ 38 ]

Prevention of Infection Through Solid Organ Donation

The most common scenario of infection via solid organ donation is the case of a seropositive donor and a seronegative recipient However, just as in the case cited above [ 37 ], the transmission of Chagas infection through organ transplantation (heart, kidneys, bone marrow, liver) was also reported relative to allegedly sero-negative donors, even in non-endemic countries

In the absence of more conclusive and informative evidence, the consensus of specialists converges towards the following prophylactic guidelines based on the serologic status of organ donors and recipients before transplantation [ 39 , 40 ] When the donor is seronegative and the recipient is seropositive, the latter’s post-operative recovery should be closely monitored for the early detection of possible infection reactivation, which might occur as a function of the immune modulation regimen required to prevent graft rejection If parasitemia intensifi es or if clinical indicators consistent with reactivation appear, etiological treatment should be initi-ated Prophylactic treatment of recipients with trypanosomicidal agents before transplantation is a less favored approach, although it is a reasonable option within the context of heart transplantation [ 41 ] Notably, not even qualitative polymerase chain reaction (PCR) techniques for the detection of parasitemia have suffi cient sensitivity to defi ne the presence of reactivation, although their negative predictive

value is adequate to rule it out Quantitative PCR techniques ( real - time PCR) are

currently used only for research purposes However, it is safe to assume that once cutoff points are established, this method will be used for the indication of preemp-tive treatment in cases with high parasitemia levels

The same principles apply when both donor and recipient are seropositive; as a rule, specifi c treatment is recommended for the donor before transplant surgery [ 28 ] Relative to heart transplantation, which is not allowed when the donor is sero-positive, relative to other organs, prior specifi c consent is required

Finally, the situation of a seropositive potential donor and a seronegative ent (in the case of living donors) is a particular cause of concern because transplantation is a priority that cannot be bypassed In such cases, it is recom-mended to administer antitrypanosomal treatment to the donor for at least 10 days (60 days ideally) to reduce or eliminate the parasitemia as well as to the recipient along with treatment for 10 days after surgery to minimize the odds of parasite inva-sion and multiplication in his/her body If the recipient becomes seropositive, standard trypanosomicidal treatment for 60–90 days is recommended [ 28 ]

Prevention of Laboratory and Hospital Accidents

Training in and compliance with the universally accepted basic principles for work

in environments in which professionals work with people or materials that are

potentially contaminated with T cruzi are the core of the prevention of transmission

through this route Ideally, the professionals should be subjected to serologic testing upon being hired by institutions in which they may be exposed to unintentional risk

If contamination is suspected, the following procedures should be adopted: ate disinfection of the eyes or skin lesions using alcohol; start prophylactic etiologi-cal treatment with the usual dose for 10 days; notify the head of the laboratory or hospital unit in which the incident occurred to avoid repetitions; and perform sero-logical testing 30 days after the event In cases of seroconversion, standard etiological treatment for 60–90 days is recommended [ 28 ]

Preventive Treatment for Cases of Congenital Transmission

Preventive etiological treatment using the currently available drugs is cated for seropositive pregnant women Pregnant women without a previous diag-nosis of Chagas disease should be subjected to serological testing Incases of positive results, the early detection of transmission to and treatment of the infected newborn infants are the basic measures [ 29 , 40 ] Newborn infants from mothers

contraindi-with known or highly suspected infection by T cruzi should be carefully examined

for signs of acute Chagas disease Additionally, parasitemia should be investigated particularly by direct examination of the umbilical cord and the infant’s blood The conventional serologic tests (based on the detection of IgG antibodies) are not indicated in this stage because the maternal antibodies remain in the infant for approximately 6 months after birth In contrast, serological tests that investigate IgM antibodies might contribute to the diagnosis because the latter are indicative

of active infection

Chagas Disease: A Neglected Disease

In confi rmed cases of congenital transmission, etiological treatment should be started immediately, which is usually well tolerated by infants

In the absence of clinical or laboratory evidence of infection, the infants should

be subjected to conventional serologic testing (investigating IgG antibodies) at age 6–8 months; only positive cases should be administered etiological treatment The infants should be then subjected to clinical and laboratory assessments once per year Persistently negative serologic results are indicative of cure of infection, which usually occurs about one year after the onset of treatment In contrast, positive results denote therapeutic failure and the infants should be treated again, preferably with a different trypanosomicidal drug [ 28 ]

Oral Transmission

Being unpredictable, primary prevention of transmission by the oral route is sible; only progressive improvement of the population’s educational and hygienic levels will allow the control of this mechanism of Chagas disease transmission Because the parasitic load is usually high, and because the mucosa of the digestive

unfea-tract is highly permeable to T cruzi , the mortality in the acute stage of infection may

be quite high Healthcare professionals should develop a high degree of diagnostic suspicion, as atypical cases with gastrointestinal bleeding and myopericarditis with large pericardial effusions are often described, to achieve effective parasitological confi rmation and to begin etiological treatment immediately Similarly, epidemio-logical surveillance should be established later on, also including the people in

contact with patients infected with T cruzi per the oral route [ 40 ]

Secondary Prevention of Chagas Disease

Independent of the route of transmission, human exposure to T cruzi exhibits three

main scenarios The fi rst, that of no infection, is based on the assumption that a quick and effi cient immune response might prevent the settlement of the parasite in the human body Infection does occur in the other two scenarios, but it may be clini-cally unapparent (scenario two) or it may manifest the signs and symptoms of the acute stage of Chagas disease (Fig 2 )

Following vector-borne exposure to T cruzi , the usual incubation period of the

acute stage is 1–2 weeks (being variable in other routes of transmission), during which the parasites in trypomastigote (fl agellate) form are detectable in the blood-stream by microscopic methods The acute stage lasts approximately 12 weeks, with most patients being asymptomatic or oligosymptomatic; because the actual cause of infection passes unnoticed, the few (unspecifi c) symptoms are attributed to other and trivial diseases, such as the fl u

The acute stage of Chagas disease is diagnosed in a very small number of patients, who exhibit signs and symptoms compatible with myocarditis or severe

meningoencephalitis Under such circumstances, the patients are at risk of death (which occurs in 5–10 % of the cases, particularly among small children or when infection is transmitted per the oral route and the parasitic load is intrinsically high) Once the acute stage ends, the parasitemia becomes practically undetectable by direct examination, even when specifi c treatment is not administered, as a function

of the protective action of the immune system Then, the chronic stage of CHD begins, with most patients remaining asymptomatic for decades, which character-izes the indeterminate form of the disease As previously noted, 40–50 % of the patients characteristically develop signs and symptoms of organ involvement 20–30 years after the acute stage of disease, corresponding to the cardiac, digestive or mixed types of CHD [ 42 ]

Secondary prevention especially targets the second and third aforementioned scenarios to hinder the progression of the indeterminate form of disease into the clinically determined types In practical terms, the aim is to avoid the manifestation

of CHD, to wit, the most formidable and frequent expression of the disease The basic strategy to achieve that goal is to provide etiological treatment to the infected individuals, its applicability depending on the active identifi cation of the largest possible number of such patients

Etiological Treatment

Although specifi c treatment is the cornerstone of the secondary prevention of Chagas

disease, only two compounds admittedly active against T cruzi are available for

clinical use, that is, benznidazole and nifurtimox Both were developed 40 years ago,

No infection

50%

40-Human

• mixed Acute Remission

Chagas disease Death

Time interval 1-2 weeks 4-12 weeks 20-30 years Lifelong

Parasitemia high low intensity, but continuous

Diagnosis detection of parasites detection of antibodies (IgG)

Etiological treatment mandatory mandatory recommended optional

Acute asymptomatic infection

Indeterminate chronic form

Determinate chronic forms

Fig 2 Progression of Chagas disease: clinical, diagnostic and therapeutic aspects [ 28 ]

Chagas Disease: A Neglected Disease

and thus, the lack of further investigation of additional drugs bears witness to the neglect of Chagas disease by the medical and scientifi c community and society at large, in this case represented by governmental agencies and the industrial sector Both available drugs have trypanosomicidal activity against the amastigote and more intensively against the circulating trypomastigote forms [ 43 ] Those agents were tested for the treatment of patients in the acute stage of infection, inducing clinical remission and parasitological and serological negative conversion (delayed)

in up to 80 % of the cases [ 44 ] Based on such evidence and in the absence of more

“defi nitive” studies, there is essentially universal agreement that etiological ment should be indicated in all patients diagnosed with acute Chagas disease, independent of the route of transmission [ 41 ] That indication is also unanimously accepted relative to episodes of reactivation in patients in the chronic stage of dis-ease, who usually exhibit natural or iatrogenic immunosuppression

However, the most propitious scenario of secondary prevention is not sented by the patients diagnosed in the acute stage of disease but by the much larger number of patients with the indeterminate form of chronic disease That crucial epidemiological fact notwithstanding, the indication for trypanosomicidal treatment

repre-in patients repre-in the chronic stage of Chagas disease [ 45 ] has been repeatedly ited and called into question, to the point that consensus is nonexistent in this regard, although it is an essential component of secondary prevention [ 41 ] This position, which is not justifi ed under the current knowledge, is largely due to an erroneous concept, according to which the main pathogenetic mechanism in Chagas disease is autoimmunity, in disregard of the fact that this was challenged long ago [ 46 ] Further arguments for that unfounded position derive from the personal experience of some physicians with the more advanced stages of disease—when, indeed, trypanosomi-cidal treatment has little to contribute—who refuse to acknowledge the evidence that, although not “defi nitive”, reasonably supports the fundamental notion that Chagas disease is, in essence, an infectious disease, the etiological agent of which remains in the human body, where it is the direct cause of a low-intensity although practically incessant infl ammatory state in some tissues, such as the myocardium Multiple and an increasing number of studies indicate that parasite persistence is the essential mechanism that accounts for the establishment of infl ammatory tissue lesions either directly or mediated by the immune system Such lesions damage the contractile myocardium and the specialized system generating and conducting car-diac electrical activity, causing cell necrosis and intensive reactive and reparative

discred-fi brosis [ 4 , 47 ] Thus, it is natural to speculate that antitrypanosomal treatment in the non-advanced chronic stage of CHD may favorably modify the natural history of the disease [ 48 ] The underlying hypothesis is that elimination, or at least reduction,

of the parasitic load may attenuate and/or delay the progression of myocarditis in the chronic stage of CHD That basic notion refl ects the theory that autoimmune aggression (disregarding the presence of parasites in the tissues) is not the decisive mechanism in the pathogenesis of CHD [ 49 ]

Although still a controversial subject, etiological treatment should be tered, as a rule, to most patients with the indeterminate and the cardiac and digestive forms of disease in the non-advanced stages [ 48 , 49 ] In some South American

countries, this indication became offi cial public health policy This recommendation

is also considered fundamental in the United States, based on studies, seminars and

a systematic literature review conducted by investigators at the Centers for Disease Control and Prevention (CDC) and Latin American collaborators [ 50 ] This position

is supported by a systematic review with meta-analysis of the few randomized ies performed with asymptomatic infected patients—presumably most of them with the indeterminate form of disease The results indicated that etiological treatment (particularly with benznidazole) is benefi cial in as much as it improves the host- parasite relationship, resulting in negative conversion of the xenodiagnosis and the

stud-reduction of circulating anti- T cruzi antibodies, as demonstrated by the serologic

tests [ 51 , 52 ] The two most conclusive studies included in that meta-analysis were performed in children; the results demonstrated seroconversion and cure of infec-tion in approximately 60 % of the participants after follow-up of 3–4 years [ 53 , 54 ] Children characteristically tolerate trypanosomicidal treatment better than adults Relative to infected individuals with clinical and laboratory abnormalities dem-onstrating established CHD, many investigators consider that specifi c treatment should still be offered, except in cases of highly advanced myocardial injury That position is based on several lines of evidence that taken together tip the balance in favor of this strategy:

• evidence resulting from experimental models of infection with T cruzi collected

by different groups of investigators, according to which etiological treatment attenuates the progression of heart disease, although complete eradication of the parasite was not attained (the parasitic load was merely reduced) [ 55 – 57 ];

• the side effects of either available trypanosomicidal agent occur less frequently and are better tolerated than was previously believed; moreover, such undesir-able effects—gastrointestinal and skin reactions, polyneuropathy, leukopenia—might be considered as tolerable and reversible, thus contrasting with the benefi cial potential of short-term treatment (2–3 months) [ 58 – 59 ];

• the results of several observational studies that assessed the effect of etiological treatment in patients with heart disease and applied clinically relevant outcome measures point to a true positive effect, with favorable modifi cation of the natu-ral history of the disease [ 60 – 64 ];

• a meta-analysis that included three randomized and six observational studies concluded that the patients treated with benznidazole exhibited signifi cant risk reduction of presenting clinical events over time compared to the patients not subjected to etiological treatment (odds ratio: 0.29; 95 % confi dence interval: 0.16–0.53) [ 65 ]

To summarize, based on the actions and individual positions of many tors [ 58 , 66 , 67 ], and on offi cial statements by agencies responsible for developing health policies, an emergent current convergence favors the position that etiological treatment should be made available to most infected patients in the chronic stage of Chagas disease [ 25 , 40 , 50 , 68 ] This perspective is based on the concept that as a function of the currently available knowledge and while still awaiting the conclusive evidence of the BENEFIT randomized study [ 69 ], the risk of incurring an alpha error

investiga-Chagas Disease: A Neglected Disease

(not to apply a promising therapeutic intervention with tolerable side effects) is much less acceptable than incurring a beta error (not to adopt something that might prove futile in the future) [ 41 ] In fact, even to basic researchers, the indifference of doctors that precludes them from even considering the possibility of indicating etio-logical treatment for their patients is questionable from an ethical standpoint [ 70 ] The implementation of effective secondary prevention measures at the popula-tion level must include active screening of children of infected mothers, relatives and other individuals exposed to infection in endemic areas Additionally, the diag-nostic opportunities provided by screening in blood banks, organ donations and job hiring processes should be maximized

New trypanosomicidal drugs may possibly become available for clinical use in the near future, whether prescribed alone or in combination with the two agents known to be effective Some of the drugs found promising in preclinical trials include posaconazole [ 71 ], ravuconazole [ 72 ] and fexinidazole [ 57 ] However, itra-conazole and allopurinol are not promising, due to the lack of suffi cient favorable evidence or clearly negative results [ 73 ]

Finally, one should hope that the supply of benznidazole and nifurtimox does not become jeopardized by management problems among the industrial suppliers [ 74 ]

Tertiary Prevention of Chagas Disease

The fundamental issue in the tertiary prevention of Chagas disease is to reduce its inherent mortality, which is the outcome exhibited by 40–50 % of the individuals

infected with T cruzi Those are the patients who, in the chronic stage, progress to

the determined cardiac, digestive and mixed forms of the disease [ 48 , 49 ] The digestive form manifests as megaesophagus and/or megacolon in 15–20 % of the cases, independent of an association with cardiovascular involvement There are no data on the mortality, specifi cally attributable to the involvement of the digestive tract, with no fully effective clinical or surgical treatment for symptoms such as dysphagia, odynophagia, constipation and malnutrition

The cardiac form is the most severe and frequent clinical manifestation of Chagas disease by far, affecting 30–40 % of the infected individuals during the many decades of progression of the chronic disease stage It is the most prevalent cardio-myopathy in Latin America and the fi rst cause of cardiovascular mortality among individuals aged 30–50 years in endemic areas [ 42 ]

The manifestations of cardiovascular involvement in the chronic stage of Chagas disease correspond to three clinical syndromes that often coexist in one and the same patient: ventricular dysfunction progressing to heart failure, rhythm disorders, and systemic and pulmonary thromboembolic complications Whereas all three syndromes contribute to the high mortality associated with Chagas disease, sudden death, which has particular clinical relevance, is signifi cantly related to arrhythmias that cause bradycardia and/or tachycardia, which frequently coexist in one and the same individual

indetermi-fi brosis—on the echocardiogram [ 76 ] and parasympathetic denervation on Holter monitoring or other autonomic tests [ 77 ] In many cases, during this stage, the patients are characteristically able to undergo intense physical exertion, manifesting vague symptoms only

In stage two, the most typical ECG abnormalities are common—complete right bundle branch block and left anterior fascicular block, whereas segmental wall- motion abnormalities most commonly affect the apical, inferoapical and inferopos-terior wall of the left ventricle Mural thrombosis of the apical aneurysm occurs in some cases

Beginning in stage three, the ECG abnormalities become more severe, including more intense bradycardia, low QRS voltage in the frontal plane leads, pathologic Q waves or the loss of the R wave in the horizontal plane leads and atrial fi brillation

• Asymptomatic • Asymptomatic ormild symptoms

• Unspecific • ECG: complete RBBB+LAFB,

electrocardiographic

monomorphic VEs, abnormalities : incomplete

abnormalities, LAFB, mild bradycardia, 2nd and 3 rd degree AVB

1 st degree AVB , discrete ST -T

• 24-h Holter: complex VAs

• NYHA class I/II

• ECG*: Q waves, • Classes II/III/IV per NYHA polymorphic VEs, • ECG*: atrial fibrillation/ considerable bradycardia, flutter

low QRS • Chest x-ray: voltage Considerable cardiomegaly

moderate-to-• Chest x-ray: mild • 2D echo: severe global

• 2D echo: mild-to-moderate • 24-h Holter: complex

• 24-h Holter: complex VAs

Sudden cardiac death

CHF Stroke

Causes of death

*in addition to the electrocardiographic abnormalities characteristic of the previous stages

2D echo= two-dimensional Doppler echocardiogram; VAs= ventricular arrhythmias; AVB= atrioventricular block;

RBBB= right bundle branch block; LAFB = left anterior fascicular block; ECG= conventional electrocardiogram;

VEs= ventricular extrasystoles; CHF= congestive heart failure; LV= left ventricle.

Fig 3 Stages and causes of death in Chagas heart disease (CHD) [ 28 ]

Chagas Disease: A Neglected Disease

The heart chambers undergo progressive global dilatation, the functional class becomes gradually worse, and in the more advanced stages, signifi cant biventricular systolic dysfunction develops, which is followed by heart failure in which the signs and symptoms of congestion are sometimes clearly predominant over the pulmo-nary signs and symptoms Perfusion defects might be detected in patients with chest pain, being initially ischemic with progression to irreversible abnormalities, which denote the presence of fi brotic areas [ 78 ]

Although ventricular arrhythmias often manifest in the early stages of disease, they become typically exacerbated parallel to the progression of the heart affl iction, being somewhat associated with the aggravation of the ventricular dysfunction Complex and multiform ventricular ectopic rhythms are a common fi nding, appear-ing in pairs or as episodes of non-sustained ventricular tachycardia, being most evident on Holter monitoring Another characteristic manifestation of CHD is sus-tained ventricular tachycardia, which might cause presyncope and syncope and progress into ventricular fi brillation with sudden death [ 79 ] This form of arrhyth-mia usually originates in reentrant micro- or macro-circuits due to the presence of

fi brosis in the lateral inferoposterior area of the left ventricle and might be reproduced in the laboratory in most patients who manifest it on electrophysiology studies with programmed ventricular stimulation [ 80 ]

Similarly, systemic and pulmonary thromboembolic events may occur, which are often found only at necropsy [ 81 ] Such events account for approximately 10 % of CHD deaths Stroke is the most frequent complication, with Chagas disease being

an acknowledged independent risk factor for cerebral embolism in areas where ease is endemic [ 82 ]

It should be emphasized that the prognosis of heart failure due to CHD is poorer compared to other causes of this condition [ 83 ] Congestive heart failure, which is a typical occurrence in stage four, causes 25 % of the deaths by CHD Nevertheless, sud-den death is the most conspicuous threat posed by CHD, as it accounts for more than

60 % of the mortality associated with this condition As a rule, sudden death occurs in the course of some physical exertion, sometimes in patients previously asymptomatic, but more often in stages two and three (Fig 3 ) More than 90 % of deaths are due to ventricular fi brillation, with the remainder of sudden deaths occurring during the state

of asystole, sometimes preceded by complete atrioventricular block

Tertiary prevention of CHD, namely, death, may now be based on the application

of a risk score that was developed and validated, also externally, in a multivariate analysis study conducted with 424 non-selected patients who were followed up for approximately 8 years on average Among other advantages, Rassi’s score includes just six variables that proved to behave as independent predictors of mortality in CHD and are assessed by means of simple clinical methods, such as 24-hour Holter monitoring, exercise testing, two-dimensional transthoracic echocardiogram, chest radiographs and conventional ECG Those variables, which are weighted to com-pound the fi nal score, are as follows: male gender, low QRS voltage, NYHA func-tional class III or IV, cardiomegaly, left ventricular dysfunction on echocardiogram and non-sustained ventricular tachycardia on Holter monitoring Based on that

score, 60 % of the patients are classifi ed as at low risk of death, 20 % as high risk and 20 % as intermediate risk [ 8 84 ]

Diagnostic Assessment of Patients with CHD

Different from the individuals infected with T cruzi who exhibit the indeterminate

form of disease, in whom the performance of one ECG test every one or two years is recommended, the patients with signs, symptoms or ECG abnormalities indicative

of CHD should be assessed by means of a detailed clinical interview and tion, chest radiographs, two-dimensional echocardiogram, 24-hour Holter monitor-ing and/or ergometric stress testing The results are used to estimate their risk of death by means of Rassi’s score Particularly in the case of patients with presyncope

examina-or syncope, 24-hour Holter monitexamina-oring might be complemented with ergometric stress testing to investigate the presence of exercise-induced arrhythmias, assess-ment of the functional capacity and the physiological chronotropic response In cases of syncope of unknown cause, seven-day Holter monitoring and intracardiac electrophysiology studies might be considered, following the aforementioned initial investigation In patients with angina, the detection of perfusion defects on myocar-dial perfusion scintigraphy is not a mandatory indication for cardiac catheterization with coronary angiography, as the coronary arteries are shown to be normal in the vast majority of the cases, whereas the clinical manifestations are, as a rule, too atypical to suggest the presence of coronary stenosis at the subepicardial level

Tertiary Prevention Therapeutic Measures

Therapy essentially aims at the prevention of the severe complications of disease, including death, refractory heart failure and disabling embolic events (e.g., embolic stroke) Additionally, patients with CHD must be treated to avoid exacerbation of the ventricular dysfunction, heart rhythm disorders and the tendency towards intra-cavitary or systemic venous thrombosis

Treatment of Ventricular Dysfunction and Heart Failure

Apparently inducing satisfactory clinical results, the treatment of evident heart failure in individuals with CHD is empirical by consensus, being based on evidence

of its benefi t in heart failure due to other causes However, in the cases that exhibit the atypical type of ventricular dysfunction found in CHD, characterized by regional dyssynergia and preservation of global systolic function, no consensus exists as to

Chagas Disease: A Neglected Disease

the need for treatment with angiotensin-converting enzyme inhibitors or beta- blockers to eventually prevent the development of heart failure

Other peculiarities of the pathogenesis and pathophysiology of CHD pose tional challenges to the treatment of heart failure to impede or delay the progression

addi-of ventricular dysfunction and its inherent mortality Thus, it is addi-often necessary to administer higher doses of diuretics, either loop or thiazide, to manage the signs and symptoms of systemic and pulmonary congestion Beta-blockers tend to be less well tolerated, particularly when used concomitantly with digoxin and amiodarone,

as a function of the aggravation of the heart electrical generation and conduction disorders, and with full doses of angiotensin-enzyme converting inhibitors, due to the greater tendency to arterial hypotension Although the extrapolation of the highly signifi cant results obtained in the treatment of heart failure by other causes is attractive, neither the effi cacy nor the effectiveness of beta-adrenergic blockers to modify the natural history of heart failure due to CHD have been demonstrated; the results of the single randomized study specifi cally performed for that purpose have not yet been communicated [ 85 ]

Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are liberally used; however, without confi rmation of their effi cacy In turn, spironolac-tone, an aldosterone inhibitor, is used based on the results of a study that demon-strated reduction of mortality among patients with heart failure by several causes, including a few dozen cases with CHD [ 86 ] Although subgroup analysis according

to cause was not performed, one further rationale underlying the empirical use of spironolactone is based on the assumption that because aldosterone blockers inhibit

fi brosis formation, they may play a relevant role in CHD, especially, in this cause of heart failure that induces most fi brosis

Cardiac resynchronization therapy was empirically used in small observational, case series studies; however, the results do not appear promising for patients with CHD because in this condition, prolonged QRS occurs more often compared to right bundle branch block

Heart transplantation represents the last alternative for many patients in very advanced stages of heart failure The results obtained in a series of patients with CHD thusly treated are particularly encouraging in comparison with other etiologies due to several reasons, and notwithstanding the previous misgivings regarding the induction

of immunosuppression in individuals with a chronic infectious disease [ 41 ]

Treatment of Heart Rhythm Disorders and Prevention

of Sudden Death

A frequent idiosyncratic occurrence in patients with CHD is the alternation of sodes of bradycardia-causing disorders with periods of sustained and more often non-sustained ventricular tachycardia In addition to the sudden death spectrum that occurs in many cases, the symptoms of presyncope, syncope, angina, dyspnea and palpitations occur that require adequate treatment Severe bradycardia is often

caused by sinus node dysfunction and atrioventricular block and less often by atrial

fi brillation with a slow ventricular response The standard treatment consists of manent pacemaker implantation, which is empirically based on the results of case series reported in the literature Ventricular tachyarrhythmias are treated with amio-darone or an automatic implantable cardioverter defi brillator (AICD) Electrophysiological mapping followed by radiofrequency catheter ablation has been described as sporadically used in patients with refractory malignant arrhyth-mias such as arrhythmic storm and incessant ventricular tachycardia; however, there

per-is no sound evidence confi rming its effi cacy [ 80 , 87 , 88 ]

The empirical use of amiodarone is recommended as fi rst-choice therapy in patients with non-sustained tachycardia or even the sustained variety without seri-ous hemodynamic repercussions (as a rule, while the global systolic function of the left ventricle is still preserved) In the absence of evidence from randomized studies, the indication of amiodarone is supported by the results of observational studies that suggest that it might increase the survival of patients with CHD at high risk of death

by arrhythmia [ 79 , 89 , 90 ]

Adequate evidence for AICD implantation is also lacking; it is recommended also empirically for patients with sustained ventricular tachycardia and serious hemodynamic repercussions, as well as for cases of recovery from sudden death [ 89 ] The discrepancy among the results of a few observational series of patients with implanted AICDs demonstrates that the singular pathophysiology of CHD poses an additional challenge to the treatment of these potentially fatal arrhythmias Additionally, it points to the need for rigorous scientifi c studies instead of the mere extrapolation of evidence gathered from patients with arrhythmias due to other causes [ 91 ] The concomitant use of amiodarone is mandatory in many cases with implanted AICDs to minimize the number of appropriate electric shocks and their deleterious consequences for myocardial contractility One randomized study com-paring treatment with AICD or amiodarone for patients with CHD at moderate and high risk of death according to Rassi’s score and with non-sustained ventricular tachycardia by Holter monitoring is currently in progress [ 92 ]

Prevention of Thromboembolic Complications

Oral anticoagulants, such as warfarin, are especially recommended for patients with CHD at high risk of developing mural or thrombi in veins that have become stagnant

as a consequence of heart failure Moreover, just as in other heart diseases, they are recommended for patients with atrial fi brillation, mural thrombi and a past history

of embolic events Due to the high emboligenic potential of CHD, a cardioembolic stroke risk score using simple clinical variables was tested in a large series of patients [ 93 ] Based on that score, patients are categorized and treated with warfarin

or acetylsalicylic acid Acetylsalicylic acid is a viable option for patients at high medical and social risk of bleeding

Chagas Disease: A Neglected Disease

Antitrypanosomal Therapy to Delay or Avoid the Progression

of Established CHD

The aforementioned medical and scientifi c arguments that support somal therapy at the secondary prevention level also partially apply to tertiary pre-vention Evidently, those principles do not apply to the advanced stages of CHD, as trypanosomicidal drugs are no longer effi cacious to halt the natural progression of the disease, in addition to causing side effects However, the recommendation for their use in many patients in less advanced stages of CHD is logical [ 48 , 50 ] However, it should be observed that a study currently in progress, meant to demon-strate that etiological therapy is benefi cial for patients in the chronic stage of Chagas

antitrypano-disease, for logistic reasons had to focus on the population infected with T cruzi that

already exhibits clinically manifest CHD [ 69 ] Any study assessing individuals with the indeterminate form of disease to test the hypothesis as formulated to explore the prevention of clinically relevant outcomes would be practically unfeasible, as a func-tion of the small number of clinical events in that patient subpopulation

To summarize, although ideal tertiary prevention of CHD remains an elusive and remote target, it is plausible to speculate that also that preventive modality contrib-uted at least partially to the remarkable reduction in the morbidity and mortality associated with Chagas disease in the past decades [ 94 ]

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© Springer International Publishing Switzerland 2015

J.P Andrade et al (eds.), Prevention of Cardiovascular Diseases,

DOI 10.1007/978-3-319-22357-5_17

Prevention and Control of Cardiovascular

Diseases: Policies, Strategies,

and Interventions

Álvaro Avezum Jr and Gabriel Pelegrineti Targueta

The epidemiological transition characterized by the increased social and economic impact of non-communicable diseases at the expense of communicable, maternal- fetal, and nutritional diseases was described by Murray and Lopez in 1997 [ 1 ] The recent publication of the updated results of the Global Burden of Disease (GBD- 2010) [ 2 ] study confi rms this trend Since the fi rst study in 1990 [ 3 ], ischemic heart disease and cerebrovascular disease have been responsible for one in four deaths in

2010 and a 17–28 % increase in the years of life lost from premature death due to these conditions was observed In the U.S., the mortality rate from cardiovascular diseases (CVD) decreased by 32.7 % between 1999 and 2009 However, one in three deaths are still caused by CVD, with an estimated cost of USD 312.6 billion

in 2009 [ 4 ] In South America, in addition to the aging population, increased ization has also played an important role in this transition The increase in popula-tion size in large cities increases the prevalence of traditional cardiovascular risk factors, including obesity, smoking, hypertension, and diabetes [ 5 ] These data are alarming when considering the vast scientifi c knowledge available for primary pre-vention and treatment of these diseases; therefore, these data should stimulate the formulation of comprehensive and effective public policies and population-based strategies

Á Avezum , Jr , M.D

Instituto Dante Pazzanese of Cardiology , Sao Paulo , Brazil

University of Sao Paulo , Sao Paulo , Brazil

Population Health Research Institute, Mc Master University , Hamilton , Canada

e-mail: aavezumjr@gmail.com

G P Targueta , M.D ( * )

Instituto Dante Pazzanese of Cardiology , Federal University of Sao Paulo , Sao Paulo , Brazil e-mail: gptargueta@gmail.com