Reading Between the Lyme: Is Borrelia Burgdorferi a Cause of Dilated Cardiomyopathy? The Debate Continues

This editorial refers to ‘Detection of Borrelia burgdorferi sensu lato in endomyocardial biopsy specimens in individuals with recent-onset dilated cardiomyopathy’, by M. Kubánek et al. doi:10.1093/eurjhf/hfs027 Lyme disease, caused by a group of spirochetes classified as Borrelia burgdorferi sensu lato (BBSL), is the most prevalent tick-borne illness in the northern hemisphere.1 Infection can lead to cardiac complications in 0.5–10% of cases, with conduction disturbances, myocarditis, and pericarditis being the most described.2 It has been hypothesized that Lyme disease may also be a cause of dilated cardiomyopathy in endemic areas. A variety of mechanisms cause dilated cardiomyopathy, including myocardial infarction and myocarditis.3,4 However, in the majority of cases, the aetiology remains idiopathic. Thus, diagnosis of Lyme disease in cases of idiopathic dilated cardiomyopathy could potentially improve the clinical outcome of patients with otherwise unknown causes of left ventricular dysfunction. Multiple studies have attempted to identify B. burgdorferi in patients with dilated cardiomyopathy by either seroreactivity or endomyocardial biopsy and to initiate treatment if there is evidence of infection. Stanek et al. published the first report of B. burgdorferi being cultured from the myocardium of a patient with dilated cardiomyopathy. Treatment with intravenous ceftriaxone produced no improvement in myocardial function.5 The same investigators observed that a cohort of patients with dilated cardiomyopathy had a higher prevalence of serum antibodies against B. burgdorferi vs. controls.6 In a subsequent study, B. burgdorferi was cultured from endomyocardial biopsy in 10 of 72 patients with dilated cardiomyopathy. However, no significant changes in left ventricular function were observed following treatment with appropriate antimicrobial therapy.7 A smaller report showed clinical improvement in eight of nine patients with dilated cardiomyopathy and seropositivity for Borrelia after treatment with intravenous ceftriaxone.8 Since these initial studies, use of serological evidence alone to show a causal link between B. burgdorferi and dilated cardiomyopathy has proven unsuccessful. In a prospective analysis from an endemic region of Minnesota, there was no significant correlation in serological status of B. burgdorferi between patients with idiopathic vs. ischaemic causes of heart failure.9 Similarly, investigators in the UK showed no significant difference in seropositivity of B. burgdorferi between patients with dilated cardiomyopathy and control groups.10 These studies suggest that serum antibodies to B. burgdorferi may not necessarily correlate with cardiac infiltration, and more sensitive molecular techniques may be needed for detection. One study analysed endomyocardial samples from 68 patients with end-stage dilated cardiomyopathy from endemic regions in Europe using qualitative polymerase chain reaction (PCR) yet failed to isolate bands of the Borrelia-specific OspA DNA in any samples.11 In contrast to these findings, recent studies using more sensitive qualitative PCR assays in combination with electron microscopy have detected B. burgdorferi in the myocardium of patients with dilated cardiomyopathy and Lyme carditis.12 Palacek et al. demonstrated detection of B. burgdorferi via qualitative PCR and electron microscopy in the myocardium of eight of 39 subjects with new-onset dilated cardiomyopathy in endemic regions of the Czeck Republic. Each patient was treated with 3 weeks of intravenous ceftriaxone, with a significant improvement in left ventricular function at 6 months.13 Although this was a small study, the results conclude that the presence of B. burgdorferi in the myocardium of patients with dilated cardiomyopathy could potentially be treated, leading to recovery of left ventricular function. In this issue of the journal, Kubánek et al. report the first study to use quantitative PCR analysis with electron microscopy to detect the B. burgdorferi genome in the myocardium of patients with new-onset dilated cardiomyopathy in endemic regions of the Czech Republic.14 The study compared 41 patients with dilated cardiomyoapthy and symptoms of heart failure of <6 months with a control group of 15 transplant patients with ischaemic cardiomyopathy and end-stage heart failure. Endomyocardial biopsies were performed on study participants and the explanted hearts in the control group. The investigators used both qualitative and quantitative PCR techniques to target the 16S rRNA, OspA, and recA gene sequences using DNA isolated from their strains of B. burgdorferi as controls. Analysis of each sample also included electron microscopy for direct visualization of spirochetes, light microscopy with histopathological and immunochemical examination for indicators of myocarditis, and assays to detect the presence of autoantibodies. Quantitative PCR of endomyocardial biopsy samples showed a significantly higher prevalence of the B. burgdorferi genome in patients with dilated cardiomyopathy compared with controls. Of the 10 patients with the B. burgdorferi genome present in their biopsy samples, 8 had a positive serology [5/8 with both positive enzyme-linked immunosorbent assay (ELISA) and western blot, 3/8 with only positive western blot], 5 out of 10 had a positive serum qualitative PCR result, and 4 out of 10 had positive electron microscopic detection of spirochetes on biopsy. Based on these diagnostic variables, the investigators determined that the test with the best positive predictive value for the presence of BBSL in endomyocardial biopsy was the combination of a western blot and qualitative peripheral serum PCR. A positive ELISA test had the lowest sensitivity at 50%. Histopathological analysis of the 10 patients showed myocyte vacuolization, hypertrophy, and interstitial fibrosis. Based on immunohistochemical analysis, only 2 out of the 10 patients met the Dallas criteria for an inflammatory cardiomyopathy. Thus, it was concluded that the observed changes in the myocardium were more indicative of chronic inflammation rather than acute myocarditis. Interestingly, a higher prevalence of previously diagnosed autoimmune disease was observed in Borrelia-positive patients with cardiomyopathy than those without. Unfortunately, treatment with intravenous ceftriaxone did not lead to a significant improvement in left ventricular function in these 10 patients. How can these results be interpreted and how does this study change the current thinking on the association between Lyme disease and idiopathic dilated cardiomyopathy? Currently, no large-scale epidemiological data exist in endemic regions of Lyme disease that would show a correlation with dilated cardiomyopathy. This study is the first to quantify the genome of B. burgdorferi in the myocardium of patients with recent-onset dilated cardiomyopathy and find a significantly higher prevalence in this population than in controls. While the authors point out the possibility that B. burgdorferi could not persist in the infarcted tissue of the control population, the data are still provocative. Previous investigations have indicated that serum analysis with ELISA and western blot can have varying predictive values for Borrelia persistence in the myocardium, thus making an association with dilated cardiomyopathy difficult to study. The current report implies that western blot and peripheral serum qualitative PCR has a high positive predictive value, with quantitative PCR of endomyocardium as the gold standard, implying a new testing strategy for future analyses. The study also provides interesting insights into the pathophysiology of dilated cardiomyopathy and Lyme disease. Quantification of Borrelia DNA in myocardial samples from this study was significantly lower than what had previously been reported in primate studies.15 In combination with the histopathology results of Borrelia-positive myocardium, this may indicate a more chronic inflammatory state possibly associated with a later stage of disease in this study population. The authors postulate that this may be why there was only a modest improvement in left ventricular function after antibiotic administration. In addition, the data indicate that a history of autoimmune disease may be linked to a greater susceptibility for developing a dilated cardiomyopathy when infected with Borrelia. Similar findings were shown in a recent report in rat and mice models indicating that there was longer myocardial persistence of B. burgdorferi in autoimmunity-susceptible animals.16 Future investigations may be aimed at identification of inflammatory factors and receptors in the myocardium to explore an autoimmune connection further. The authors report a very thorough analysis that shows a significantly higher prevalence of the B. burgdorferi genome in patients with new-onset dilated cardiomyopathy when compared with controls in an endemic region of the Czeck Republic. While this was a small study, it provides a foundation for larger epidemiological analyses, biomolecular investigation of inflammatory and infectious mechanisms, and larger control trials for antibiotic treatment. These results solidify the concept of an association between Lyme disease and idiopathic dilated cardiomyopathy. Conflict of interest: none declared.