International Journal of Cardiology 129 (2008) 15 – 21 www.elsevier.com/locate/ijcard Review Cardiac implications of Lyme disease, diagnosis and therapeutic approach Pavlos Lelovas a , Ismene Dontas a , Eleni Bassiakou b , Theodoros Xanthos b,⁎ a b Laboratory for Research of the Musculoskeletal System, University of Athens, School of Medicine, Greece Department of Experimental Surgery and Surgical Research, University of Athens, School of Medicine, 15B Agiou Thoma Street, 11527 Athens, Greece Received 17 May 2007; received in revised form 20 September 2007; accepted 14 January 2008 Available online 27 May 2008 Abstract Lyme is a tick-borne disease. The genetic diversity of Borreliae its distribution worldwide and its epidemiology have been related to different clinical manifestations. Carditis is a rare manifestation of Lyme disease. The commonest abnormality is atrioventricular block of various degrees, though other rhythm abnormalities have been reported. Pericarditis, myocarditis, cardiomyopathy and degenerative valvular disease have been associated with B. burgdorferi. Temporary pacing might be required in unstable patients. The majority of the conduction disturbances have a benign prognosis, if the infectious agent is identified and treated appropriately. © 2008 Elsevier Ireland Ltd. All rights reserved. Keywords: Lyme carditis; Ixodes; Atrioventricular block; Doxycycline; Pacing 1. Introduction Lyme borreliosis is the commonest tick-borne disease in the northern hemisphere [1]. The characteristic cutaneous lesion of Lyme disease is erythema migrans [2,3,4]. Lyme disease was first recognized in epidemic form in Lyme, Connecticut, where 59 cases appeared in a year. It was Steere who characterized the disease [5]. However the precise etiology was resolved in 1982 when spirochetes were cultured from ticks [6], and later from the skin, blood and spinal fluid of infected patients [7,8]. Although Lyme disease is known to affect primarily the skin, heart, nervous system, and joints, the cardiac manifestation that occur in 0.5% to 10% of cases in Europe and North America [9–11], remain the least well-documented, with conduction and rhythm disturbances noted more frequently, and possibly other cardiac diseases, such as cardiomyopathy, myocarditis, pericarditis and degenerative cardiac valvular disease [12,13]. The aim of the present review is to present different cardiac implications of Lyme disease, to associate the ⁎ Corresponding author. Tel.: +30 2107462500. E-mail address: theodorosxanthos@yahoo.com (T. Xanthos). 0167-5273/$ - see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2008.01.044 diversity of the clinical manifestations to the genomic diversity of Borrelia, and to elucidate the obscure diagnosis of Lyme disease suggesting a therapeutic algorithm. 2. Epidemiology Borrelia belongs to the spirochete family, which is grouped in the Borrelia burgdorferi sensu lato species complex. Because of the wide genetic diversity, it is further subdivided into at least 11 genomic species [14], and even so an intraspecific variability has also been observed [15]. Recently a new genomic species has been isolated from patients in Europe constituting the 12th member of the complex [16]. The primary established vectors of the disease are various species of the genus Ixodes, a three-host hard tick, whose larvae and nymphs feed on small mammals, birds, and reptiles according to its species [17]. In Europe the main vector is I. ricinus, which is also responsible for the transmission of other tick-borne diseases, such as tickborne encephalitis virus, Anaplasma phagocytophilum, Babesia microtii, Babesia divergens and others [18]. In Eurasia the main vector of the disease is I. persulcatus and in North America I. scapularis and I. pacificus [19–22]. Ixodes 16 P. Lelovas et al. / International Journal of Cardiology 129 (2008) 15–21 uriae, which parasitizes seabirds, might be responsible for the transmission of Borrelia across the world [23] (Table 1). The distribution of Borrelia worldwide is related to the Ixodes ticks and the presence of a competent reservoir host. It has been found that some genospecies are strictly related to a specific host. This could explain why some genospecies are more prevalent in some regions, where its specific host is abundant. This specificity has been hypothesized to be derived from the ability of the hostcomplement to lysate some of the Borreliae genospecies [24]. On the other hand there are some genospecies, which are resistant to the complement of more than one host, infecting them and this might be a reason for a broader distribution worldwide [25]. From the domestic mammals, dogs are known to be susceptible to the disease. Dogs pose a minimal risk to human health, and it seems that their main part in the epidemiology of the disease is that they bring ticks and humans in close proximity. Although cats have been infected experimentally, it is not clear if they are susceptible to the natural disease [17]. It has been demonstrated that the tick saliva activates the transmission of Borreliae [26]. The time needed, from the attachment of the tick, for Lyme disease to be transmitted seems to vary between Europe and North America. In North America, this transmission occurs 48 h after the tick attachment, whereas in Europe the time might be shorter than 24 h [18]. Because of the variety in the epidemiology, ecology, and clinical manifestation of Lyme disease between Europe and North America, many investigators supported that there is an association between the different genomic types of Borreliae and their distribution worldwide, as well as the clinical manifestation of the disease [27]. The genospecies of Borrelia established to be pathogenic to humans are Borrelia burgdorferi senso stricto, Borrelia afzelii and Borrelia garinii. The first type is the only pathogenic to humans in North America, while in Europe all three types have been isolated from humans suffering from the disease. Other genospecies incriminated to be pathogenic to human in Europe are B. valaisiana, B. lusitaniae, B. bissettii and B. spielmanii or B. genospecies A14S which has been identified lately. B. bissettii has been isolated from patients in Europe and though it has been isolated from ticks in the USA it has never been proven pathogenic. The aforementioned genospecies have been associated with different clinical symptoms in patients [18,28–32] (Table 1). 3. Stages of the disease The clinical manifestation of the disease is divided into three stages. In the 1st stage, or the acute illness, at the site of the tick bite, the Borreliae multiply and spread into the dermis [12]. The resulting skin lesion is called erythema migrans. Other symptoms in the acute phase of the disease are lymphadenitis and other systemic symptoms such as headache, fever, malaise, myalgia and arthralgia. In the 2nd stage, or the dissemination phase, which occurs weeks to months later, the Borreliae spread hematogenously and they can cause secondary annular skin lesions, migratory arthritis, cardiac arrhythmias, and meningitis. In this stage antibodies develop. At the 3rd stage or late chronic phase, 2 to 3 years after the initial infection the clinical signs are destructive chronic arthritis, acrodermatitis chronica atrophicans and neuropathy. In this stage, the overzealous immune host reaction is hypothesized to be against its own proteins, which resemble the heat-shock proteins of the Borreliae [33] (Table 2). 4. Cardiac implications Lyme carditis is a rare manifestation of the disease, occurring in 1.5%–10% of cases in North America and 0.5%–4% in Europe [27]. Whereas there is no sex predisposition for Lyme disease, Lyme carditis has been reported to have a 3:1 male:female ratio [34]. Lyme carditis is not the only clinical manifestation with sex predisposition [35,36]. The cardiac implications of Lyme disease can be Table 1 Different genospecies of B. burgdorferi and their distribution and clinical manifestation accordingly Borrelial genomic type Vector Geographic region Clinical manifestation B. burgdorferi senso stricto Ixodes scapularis USA Erythema migrans, arthritis, carditis, neuroborreliosis, acrodermatitis chronica atrophicans Ixodes ricinus Ixodes ricinus Ixodes persulatus Ixodes ricinus Europe Europe China Europe Ixodes persulatus Ixodes ricinus Ixodes ricinus Ixodes ricinus Ixodes pacificus Asia Europe Europe Europe (Slovenia) USA Europe (Netherlands, Germany) B. garinii B. afzelii B. valaisiana B. lusitaniae B. bissettii B. spielmanii or B. genospecies A14S Erythema migrans, arthritis, neuroborreliosis Not reported Erythema migrans, arthritis, Neuroborreliosis, acrodermatitis chronica atrophicans. Not reported Erythema migrans, arthritis, neuroborreliosis Isolation from a patient with Lyme disease in Portugal Erythema migrans, Lymphocytoma Not reported Erythema migrans. 17 P. Lelovas et al. / International Journal of Cardiology 129 (2008) 15–21 Table 2 Clinical stages of Lyme disease and methods of laboratory diagnosis Clinical manifestation Methods of direct detection Serological examination Stage I Acute illness Erythema migrans Stage II Dissemination phase Weeks to months later Secondary annular skin lesions Culture and PCR from skin biopsies 50–70% sensitivity Culture and PCR from skin biopsies 50–70% sensitivity 20–50% sensitivity Predominance of IgM antibodies 70–90% sensitivity In case of early stage II IgM predominate while in late Stage II IgG predominate Lyme carditis Neuroborreliosis Stage III Late chronic phase Years later Chronic arthritis Acrodermatitis chronica atrophicans Chronic neuroborreliosis Endomyocardial biopsies Culture or PCR from Cerebrospinal fluid 10–30% sensitivity PCR from Synovial biopsy 50–70% sensitivity Culture and PCR from skin biopsies 50–70% sensitivity Approximately 100% sensitivity Predominance of IgG antibodies From references [14,16,33]. categorized into: conduction disturbances and other pathologies of the heart. 4.1. Conduction disturbances The most frequent conduction disturbance is atrioventricular (AV) block. Van der Linde comparing 105 cases reported that third degree AV block has been present in 49% of patients with Lyme carditis, compared to 16% with second-degree and 12% with first degree AV blocks [34]. Another report suggests that 98% of the patients with AV conduction disturbances had at some time during the course of the disease first degree AV block, while Weckebach periodicity occurred in 40% and complete AV block in 50% [37]. Progression from first degree to third degree AV block can occur within minutes [38]. The patients developing first degree AV block with a PR interval greater than 0.3 s have a higher risk to develop complete AV block [10,37]. The site of the conduction block occurs at, or above, the AV node, especially within the AV conduction system, though sinoatrial and intraatrial conduction disturbances have also been described [2,10,37,36]. AV blocks usually resolve within 6 weeks, probably because of regression of the underlying inflammation [37,38]. AV blocks, sinoatrial and intraatrial conduction disturbances predict a benign prognosis [37]. However, there are also other conduction disturbances in Lyme disease with unfavorable prognosis: i) Escape rhythms with severe AV block that are slow and of wide QRS pattern. ii) Transient lack of any escape-rhythms, with brief asystoles. iii) Fluctuating bundle branch block depicting either transient His-Purkinje involvement or intranodal atrioventricular block [39–44]. The frequency of conduction disturbances in children with no evidence of cardiac clinical manifestation has been found to be 29%. The most frequent electrocardiographic abnormality was first degree AV block, while left axis deviation, prominent sinus dysrhythmia, sinus bradycardia, wandering atrial pacemaker and ectopic atrial bradycardia have been noted less frequently [45]. 4.2. Other cardiac complications There is evidence that pericarditis might be a cardiac manifestation of Lyme disease [46]. Pericardial effusion, consisting of exudate containing few neutrophils and lymphocytes, has been correlated to Lyme disease. The effusion resolves after pericardiocentesis and administration of antibiotics against B. burgdorferi [47]. B. burgdorferi has also been isolated from the myocardium of a patient with an unexplained dilated cardiomyopathy [48]. In a study where patients with dilated cardiomyopathy, and seropositive to B. burgdorferi, were treated with ceftriaxone, experienced significant improvement in left ventricular ejection fraction [49]. An untreated patient with Lyme disease, and a late debut of carditis showed initially fluctuating diffuse T wave inversions. The left ventricular ejection fraction was diminished and the chest X-rays showed cardiomegaly. All of the symptoms resolved after administration of antibiotics against Borrelia, suggesting that this could be a case of an early stage of a dilating cardiomyopathy [50]. On the other hand, researchers from North America were unable to detect such an association. Suedkamp et al. examined heart tissue and sera of patients undergoing cardiac transplantation, for the presence of B. burgdorferi by Polymerase Chain Reaction (PCR) and standard serology. Furthermore, in a prospective study conducted by Sonnesyn et al., sera was examined from a group of patients with dilated cardiomyopathy, ischemic heart disease and healthy controls for B. burgdorferi. In both studies there was no evidence of an association between B. burgdorferi and endstage dilated cardiomyopathy [51,52]. A case report from Cavner suggests a possible relationship of degenerative cardiac valvular disease to Lyme borreliosis. The patient developed initially moderate mitral 18 P. Lelovas et al. / International Journal of Cardiology 129 (2008) 15–21 insufficiency, which progressed to severe, and rupture of the chordae. After surgical replacement of the mitral valve the patient presented with pericardial effusion. A thorough laboratory investigation incriminated Lyme disease as the only possible etiological agent [13]. Other reported cardiac manifestations of Lyme disease are episodes of non-sustained ventricular tachycardia, ST segment depression, reversible depression of left ventricular function and congestive heart failure [12,53]. Furthermore, asymptomatic B. burgdorferi seropositive adults have been reported to have lower resting heart rates than seronegative ones [54]. 5. Pathology of Lyme carditis The mechanism by which Lyme disease affects the conduction system has been proposed to be the result of the direct dissemination of spirochetes into cardiac tissues, the inflammatory response associated with the infection or both, though the discordance between the scant organisms of Borreliae discovered at histopathology, and the extent of the inflammatory response, suggests an immunologic component of the host reaction [12,55]. In an experimental study on a murine model of Lyme carditis and arthritis there was evidence of autoimmune-mediated mechanism. It is possible that cross-reactive IgM antibodies, triggered initially to B. burgdorferi antigens, react to self-components through the phenomenon of mimicry [56]. Concerning the pathological lesions in Lyme carditis the most common finding is transmural inflammatory infiltrate, which in the endocardium, has a characteristic band-like appearance and consists mainly of lymphoid cells. Small nodules of neutrophils and macrophages can also be seen in the hyper-acute disease, with myocyte necrosis evident in some cases [57]. Endocardial and interstitial fibrosis may be prominent. Myocardial fiber degeneration has also been described. The pathogenic agent may be found near or in the inflammatory infiltrates, between the muscle fibers and in the endocardium [58]. Lesions suggestive of vasculitis may be seen in small and large vessels in the myocardium. Small vessels show endothelial swelling, whereas large vessels adventitial infiltrate with loose reticulin and increased deposition of collagen. In a patient with signs of pericardial constriction, fibrinous pericarditis has also been documented [59]. 6. Diagnosis Diagnosing Lyme carditis can be very challenging. Although erythema migrans is a very specific symptom of Lyme disease in the acute phase, it is not present in all cases. Ticks' bite in combination with the rest of the symptoms in Lyme carditis is very suggestive of the disease, but not all the patients recall or mention such a bite [36,60,61]. Therefore, there is a need of a sensitive and specific test for the diagnosis of the disease. The most specific examination is the culture of B. burgdorferi, but there are several limitations through this approach [8,62,63]. Even though isolation of the Borreliae have been reported from various tissues and fluids, high sensitivity can mainly be achieved through skin biopsies of Erythema migrans or acrodermatitis chronica atrophicans of untreated patients. Other limitations are the time needed for the culture to reveal its results, the low sensitivity of the method, in all other than the cutaneous manifestation of the disease and the expense. For these reasons and albeit culture has been very revealing especially in recognition of the specific genospecies of B. burgdorferi in research studies, culture has not been put in routine clinical practice as a diagnostic tool [14,16]. PCR can be very helpful, since it detects directly the genetic material of Borreliae in multiple tissues. Another advantage of the method is that it can determine the different genomic types of Borreliae, which is especially significant in Europe, where seven different genospecies have been described and the pathogenity of the four of them has not been proven yet [18,31,32]. PCR is more sensitive after tissue examination. Its sensitivity is similar to culture when sampling the skin, while it surpasses culture sensitivity in Lyme arthritis especially when samples are taken from synovial tissue [14]. Transvenous endomyocardial biopsy can be indicative of Lyme carditis. The band-like infiltrate is strongly suggestive and it can be seen, even if the quality of the specimen is limited [58]. The intrinsic limitation (sampling error, invasiveness of the method, variability of interpretation) restrains the use in the clinical practice [64]. Serologic examination is readily available in the clinical setting. The most frequently used assays are: enzymelinked immunosorbent assay (ELISA), immunofluorescence assays and Western blotting [65,66], but falsenegative and false-positive results may be obtained [67– 69]. This is the reason why in the USA, a two-step protocol for the evaluation of B. burgdorferi antibodies in sera has been recommended [69]. The first step follows a screening assay, preferably ELISA and in case of seropositivity or equivocal result, a confirmatory Immunoblot test should be performed [70]. In both ELISA and Immunoblot assays the antigens used, should detect both IgM and IgG antibodies. Immunoblot should have high specificity of at least 95%. Serological diagnosis of Lyme disease in Europe should take into account the heterogeneity of the causative agent [14]. While in the USA a consensus has been reached about the criteria used for the validation of the Immunoblot, these criteria cannot be applied in Europe [71]. In the early stages of the disease serological tests may reveal false-negative results in a high percentage. Usually IgM antibodies are more prevalent in the early stages while IgG in the late stages of the disease. P. Lelovas et al. / International Journal of Cardiology 129 (2008) 15–21 19 Fig. 1. Therapeutic algorithm of patient with Lyme carditis. ⁎ Doxycycline is contraindicated in children under the age of 8 years old, pregnant and breastfeeding women. Interpretation should always be done in the context of clinical presentation [16] (Table 2). If a patient is found positive for Lyme disease, he should be further investigated for other tick-borne diseases, since there are many epidemiological studies suggesting that cotransmission is possible [72,73]. 7. Therapeutic approach Antibiotic therapy in the early stages of the disease has been reported to prevent, or ameliorate later complications [12]. Patients with minor cardiac involvement (first degree AV block with PR interval b 0.3 s) could be treated orally with doxycycline, amoxycillin, or cefuroxime [74]. Administration of doxycycline in all adults, except pregnant, breastfeeding women and children under the age of 8, [75] is preferable because of its higher efficacy to other tick-borne diseases that could be co-transmitted [72,76,77] and aggravate the outcome of these cases [78]. Patients with more severe conduction system disturbances (first degree AV block with a PR interval N 0.3 s, second or third degree AV block) should be hospitalized in a coronary care unit and administered either intravenous ceftriaxone or high-dose intravenous penicillin G. Customary administration of non-steroidal anti-inflammatory drugs or steroids in advanced AV block has the disadvantage of precipitating the recurrence of central nervous system and joint symptoms after withdrawal of the drugs. Temporary cardiac pacing may be required in up to a third of cases of Lyme carditis and complete recovery occurs in greater than 90% of patients [79] (Fig. 1). Permanent pacing was required in one case of a refractory AV block to aggressive pharmacological therapy. In all other cases, permanent pacemakers were inserted prior to the definitive diagnosis of Lyme disease [37,74,80–83]. 8. Conclusion Lyme carditis is a rare complication of Lyme disease. 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