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ISHLT International Traveling Scholarship Report


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Mrinalini Krishnan, MD
Guthrie Robert Packer Hospital
Sayre, PA, USA
Krishnan.mri@gmail.com



As a member of the International Society of Heart and Lung Transplantation (ISHLT), I was awarded the ISHLT Traveling Scholarship and granted the opportunity to visit Brazil and learn about Chagas cardiomyopathy and heart transplantation from the team at the Heart Institute (InCor), University of São Paulo Medical School. First described by Brazilian physician Dr. Carlos Chagas over 100 years ago, Chagas disease is a fascinating entity that has afflicted 6 million people in Central and South America. Generated by the protozoan parasite Typanosoma cruzi and predominantly transmitted by the reduviid bug through fecal contact with mucous membranes or breaks in the skin, this disease is credited for 300,000 newly reported cases each year. Approximately 20-30% of infected patients progress to develop cardiac damage and cardiovascular complications including Chagasic cardiomyopathy, the most common and most severe manifestation of this disease process, which is almost always progressive. Other cardiac complications include bradyarrhythmias, ventricular arrhythmias, sudden cardiac death and cardiogenic shock. The growing migrant population from Latin America, where Chagas disease is endemic, has led to a gradually increasing prevalence of Chagas throughout the world with approximately 400,000 patients currently afflicted with T. Cruzi infection in non-endemic countries, predominantly the United States and Europe.

links imageThe direct challenges faced in the management of Chagas cardiomyopathy patients include initial trypanocidal therapy, supportive congestive heart failure therapies and ultimately heart transplantation, with pre-transplant optimization of the Chagas infection and post-transplant immunosuppression in conjunction with infection management. The implications of the large number of Chagas infected migrants are becoming more recognized as a world health issue, with recent publications describing care protocols used by experienced medical centers and calling for universal registries to aid in facilitating the international exchange of this knowledge. As such, I sought to thoroughly grasp the facets of this disease process and its effective management, through the progression into and following heart transplantation, and subsequently share this information with the ISHLT community. With high volumes of fifty adult and twenty pediatric heart transplantations in the past year, over 25% of which were indicated for Chagasic cardiomyopathy, Dr. Fernando Bacal and his highly skilled heart transplant team at InCor have a deep familiarity with the longitudinal care of these challenging patients. The variation in treatment options and lack of clinical trial-based standardization in this disease entity also encouraged me to travel to learn from an institution that has utilized their wealth of knowledge and experience to effectively manage their vast Chagas patient cohort over the years.

Upon my arrival at InCor, a 500-bed facility that exclusively treats cardiovascular and pulmonary disorders within the public health system in Brazil, I quickly learned that their team really is a tremendous example of the importance of multi-specialty collaboration for the efficient and efficacious treatment of complex disease processes. During my time at their institution, I was fortunate to work with a number of experts in their respective specialties who have had extensive exposure to Chagas disease patients. To illuminate the intricacies of Chagas disease as well as the infectious processes warranting attention in Chagas cardiomyopathy patients, I met with Infectious Disease Specialist of Tropical Diseases, Dr. Tânia Mara Varejão Strabelli, who described the classic manifestations of Chagas cardiomyopathy and their implications. One in three patients treated with chronic Chagas cardiomyopathy are noted to develop acute Chagas reinfection during their post-heart transplantation period. Acute Chagas infection in this patient population most commonly presents as myocarditis or cutaneous lesions. Confirmation of the presence of infection is done through biopsy, with all samples examined under direct exam, culture and using the polymerase chain reaction (PCR) method. In the rarer meningoencephalitis, the cerebral spinal fluid does not usually test positive for Chagas present, and therefore, definitive diagnosis must be obtained through brain biopsy. When manifested in the form of myocarditis or cutaneous lesions, patients can successfully be treated with a 2-month course of anti-parasitic benznidazole or nitrofurtimox, while the more severe reactivation as meningoencephalitis requires a longer 9-month course for resolution.

To further expand on the pathology involved with Chagas cardiomyopathy, concomitant Toxoplasmosis and the implications of immunosuppression and reactivation of Chagas disease post-transplantation, I met with pathologist, Dr. Luiz Alberto Benvenuti, and observed case samples of a variety of clinical challenges. The pathophysiologic progression of Chagas cardiomyopathy involves the hypertrophy of the cardiac sarcomeres in parallel, in contrast with hypertrophy in series noted in dilated cardiomyopathy. The pathognomonic pathologic presentation of Chagas cardiomyopathy is the presence of left ventricular apical wall thinning with inferior wall involvement also noted at times. Lymphohistiocytic infiltration due to myocarditis results in patchy, fine fibrosis throughout the left ventricle, which can provoke ventricular arrhythmias. Another common presentation is the "Chagasic rosary," noted as white spotty lesions over the coronary arteries with associated fibrosis. An interesting challenge faced in this immunosuppressed patient population is making the distinction between Toxoplasmosis infection and Chagas reactivation. Though the clinical presentation of patients or even the evaluation of samples under gross examination may appear indistinguishable, under microscopic examination, Toxoplasmosis appears as a cyst with a membrane, while Chagas in contrast, has a pseudocyst with no membrane present. This important microscopic characteristic can therefore guide us toward the appropriate management of Toxoplasmosis or Chagas accordingly.

A major challenge in Chagasic cardiomyopathy patients post-heart transplantation is maintaining the balance between adequate immunosuppression to prevent organ rejection and anti-parasitic treatment to limit reactivation of Chagas disease. The Immunology department at InCor plays an integral role in the pre- and post-transplant care of Chagasic cardiomyopathy patients and has formulated their own antibody against T. cruzi to aid in the process. Using paraffin embedded and formalin fixed samples, T. cruzi parasites within myocardial cells or skin histiocytes are found in the amastigote form, while the trypomastigote form can be seen in blood and fluid samples. The definitive diagnosis of Chagas disease is through confirmation of the presence of a parasite. Ultimately, when unable to adequately establish the presence of parasite to confirm reactivation, the decision is understandably made to err on the side of caution and treat patients for active organ rejection. The team at InCor has also discovered that the use of azathioprine in place of mycophenolate for immunosuppression in Chagasic patients post-heart transplantation has decreased the reactivation of latent Chagas disease 6-fold and have therefore incorporated azathioprine as part of their standard immunosuppression regimen for this distinct population.

A notable observation during my visit to Brazil was the stark contrast between the public health system and private hospital system. Being part of the public healthcare system, the team at InCor faces unique and unfortunate challenges in providing heart transplantation to patients in a system with limited resources. Despite cost limiting the use of ventricular assist devices, implantable cardiac resynchronization, cardioverter defibrillator devices and even certain medications, the InCor team has streamlined their peri-transplant process for patient care with excellent success rates. Adhering to the adage of necessity being the mother of invention, their team has even worked to create their own more cost-effective temporary ventricular assist device, aptly named InCor, to utilize as cardiac support therapy for pre-transplant patients. By incorporating their system-based approach, I truly feel that the heart transplant team in São Paulo has effectively implemented a holistic and inclusive manner in which they provide care to each of their patients.

Overall, I feel very appreciative and honored to have been awarded this once-in-a-lifetime opportunity to learn from those at the forefront in the field managing peri-transplant Chagas cardiomyopathy. As medical care providers around the world, we must be cognizant that our Latin American migrant patients are at risk of having underlying Chagas disease and in turn, be aware of the nuances to look for when evaluating and caring for such patients. I am truly grateful to the ISHLT and Dr. Bacal's team at InCor for contributing to my education and allowing me to disseminate my gained knowledge to our medical community, and I wholeheartedly encourage my ISHLT colleagues to also try to take advantage of this exceptionally unique scholarship award. ■

Disclosure Statement: The author has no conflicts of interest to disclose.


References:

  1. Bacal F et al. Transplantation for Chagas' Disease: An Overview of Immunosuppression and Reactivation in the Last Two Decades. Clin Transplant. 2010;24(2):E29-34.
  2. Bacal F et al. Mychophenolate mofetil Increased Chagas Disease Reactivation in Heart Transplanted Patients: Comparison Between Two Different Protocols. Am J Transplant. 2005;5(8):2017-21.
  3. Benatti RD et al. Heart Transplantation for Chagas Cardiomyopathy. J Heart Lung Transplant. 2017;36(6):597-603.
  4. Benvenuti A et al. Trypanosoma cruzi Persistence in the Native Heart is Associated with High-Grade Myocarditis, But Not with Chagas' Disease Reactivation After Heart Transplantation. J Heart Lung Transplant. 2014;33(7):698-703.
  5. Bern C, Montgomery SP. An Estimate of the Burden of Chagas Disease in the United States. Clin Infect Dis. 2009;49(5):e52-e54.
  6. Bern C. Chagas' disease. N Engl J Med. 2015;373:456-66.
  7. Bocchi, EA et al. Chronic Chagas Heart Disease Management: From Etiology to Cardiomyopathy Treatment. J Am Coll Cardiol. 2017;71(12):1510-24.
  8. Bonney KM. Chagas disease in the 21st century: a public health success or an emerging threat? Parasite. 2014;21:11.
  9. Mora G. Chagas Cardiomyopathy. Eur Soc Card - E-Jour Card Practice. 2016;14:31.



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