Mitochondrial DNA haplogroups and variants predispose to chagas disease cardiomyopathy

Cardiomyopathies are major causes of heart failure. Chagas disease (CD) is caused by the parasite Trypanosoma cruzi, and it is endemic in Central and South America. Thirty percent of cases evolve into chronic chagas cardiomyopathy (CCC), which has worse prognosis as compared with other cardiomyopathies. In vivo bioenergetic analysis and ex vivo proteomic analysis of myocardial tissues highlighted worse mitochondrial dysfunction in CCC, and previous studies identified nuclear-encoded mitochondrial gene variants segregating with CCC. Here, we assessed the role of the mitochondrial genome through mtDNA copy number variations and mtDNA haplotyping and sequencing from heart or blood tissues of severe, moderate CCC and asymptomatic/indeterminate Chagas disease as well as healthy controls as an attempt to help decipher mitochondrial-intrinsic genetic involvement in Chagas disease development. We have found that the mtDNA copy number was significantly lower in CCC than in heart tissue from healthy individuals, while blood mtDNA content was similar among asymptomatic Chagas disease, moderate, and severe CCC patients. An MtDNA haplogrouping study has indicated that African haplogroups were over represented in the Chagas subject groups in comparison with healthy Brazilian individuals. The European lineage is associated with protection against cardiomyopathy and the macro haplogroup H is associated with increased risk towards CCC. Using mitochondria DNA sequencing, 84 mtDNA-encoded protein sequence pathogenic variants were associated with CCC. Among them, two variants were associated to left ventricular non-compaction and two to hypertrophic cardiomyopathy. The finding that mitochondrial protein-coding SNPs and mitochondrial haplogroups associate with risk of evolving to CCC is consistent with a key role of mitochondrial DNA in the development of chronic chagas disease cardiomyopathy.

Epigenetic regulation of transcription factor binding motifs promotes Th1 response in Chagas disease cardiomyopathy.

Chagas disease, caused by the protozoan Trypanosoma cruzi, is an endemic parasitic disease of Latin America, affecting 7 million people. Although most patients are asymptomatic, 30% develop complications, including the often-fatal Chronic Chagasic Cardiomyopathy (CCC). Although previous studies have demonstrated some genetic deregulations associated with CCCs, the causes of their deregulations remain poorly described. Based on bulk RNA-seq and whole genome DNA methylation data, we investigated the genetic and epigenetic deregulations present in the moderate and severe stages of CCC. Analysis of heart tissue gene expression profile allowed us to identify 1407 differentially expressed transcripts (DEGs) specific from CCC patients. A tissue DNA methylation analysis done on the same tissue has permitted the identification of 92 regulatory Differentially Methylated Regions (DMR) localized in the promoter of DEGs. An in-depth study of the transcription factors binding sites (TFBS) in the DMRs corroborated the importance of TFBS's DNA methylation for gene expression in CCC myocardium. TBX21, RUNX3 and EBF1 are the transcription factors whose binding motif appears to be affected by DNA methylation in the largest number of genes. By combining both transcriptomic and methylomic analysis on heart tissue, and methylomic analysis on blood, 4 biological processes affected by severe CCC have been identified, including immune response, ion transport, cardiac muscle processes and nervous system. An additional study on blood methylation of moderate CCC samples put forward the importance of ion transport and nervous system in the development of the disease.

Epigenetic regulation of transcription factor binding motifs promotes Th1 response in Chagas disease cardiomyopathy

Abstract: Chagas disease, caused by the protozoan Trypanosoma cruzi, is an endemic parasitic disease of Latin America, affecting 7 million people. Although most patients are asymptomatic, 30% develop complications, including the often-fatal Chronic Chagasic Cardiomyopathy (CCC). Although previous studies have demonstrated some genetic deregulations associated with CCCs, the causes of their deregulations remain poorly described. Based on bulk RNA-seq and whole genome DNA methylation data, we investigated the genetic and epigenetic deregulations present in the moderate and severe stages of CCC. Analysis of heart tissue gene expression profile allowed us to identify 1407 differentially expressed transcripts (DEGs) specific from CCC patients. A tissue DNA methylation analysis done on the same tissue has permitted the identification of 92 regulatory Differentially Methylated Regions (DMR) localized in the promoter of DEGs. An in-depth study of the transcription factors binding sites (TFBS) in the DMRs corroborated the importance of TFBS's DNA methylation for gene expression in CCC myocardium. TBX21, RUNX3 and EBF1 are the transcription factors whose binding motif appears to be affected by DNA methylation in the largest number of genes. By combining both transcriptomic and methylomic analysis on heart tissue, and methylomic analysis on blood, 4 biological processes affected by severe CCC have been identified, including immune response, ion transport, cardiac muscle processes and nervous system. An additional study on blood methylation of moderate CCC samples put forward the importance of ion transport and nervous system in the development of the disease.

COVID-19 complicating perioperative management of LVAD implantation: A case report and systematic review.

The coronavirus 2019 disease (COVID-19) affected 125 million people worldwide and caused 2.7 million deaths. Some comorbidities are associated with worse prognosis and left ventricular assist device (LVAD) recipients are probably part of this high-risk population. We report a 31-year-old male patient who developed COVID-19 during LVAD implantation. His postoperative period was complicated by severe pneumonia and mechanical ventilation (MV) leading to right ventricular failure (RVF) and inotrope necessity. He experienced multiple complications, but eventually recovered. We present a systematic review of LVAD recipients and COVID-19. Among 14 patients, the mean age was 62.7 years, 78.5% were male. A total of 5 patients (35.7%) required MV and 3 patients (21.4%) died. A total of 2 patients (14.2%) had thromboembolic events. This case and systematic review suggest LVAD recipients are at particular risk of unfavorable outcomes and they may be more susceptible to RVF in the setting of COVID-19, particularly during perioperative period.

First case of extracorporeal membrane oxygenation in cardiorespiratory arrest in an emergency room in Brasil: a possible reality?

The extracorporeal membrane oxygenation (ECMO) is a procedure that has been used for a long time in reference centers worldwide. Its fundamental precept is to serve as a bridge to a definitive treatment in patients with severe, but potentially reversible, clinical conditions. Despite this, its use in cardiopulmonary arrest (ECPR) is still a matter of debate, especially when indicated in the emergency department. There is not yet a sufficient level of evidence to support its routine use. In Brasil, the procedure stopped being considered an experimental technique by the Federal Council of Medicine only in 2017. The objective of the present case is to share the pioneering spirit of a Brazilian reference center with ECPR in the emergency room and to discuss the future challenges of the ECMO technique.

First case of extracorporeal membrane oxygenation in cardiorespiratory arrest in an emergency room in Brasil: a possible reality?

SUMMARY The extracorporeal membrane oxygenation (ECMO) is a procedure that has been used for a long time in reference centers worldwide. Its fundamental precept is to serve as a bridge to a definitive treatment in patients with severe, but potentially reversible, clinical conditions. Despite this, its use in cardiopulmonary arrest (ECPR) is still a matter of debate, especially when indicated in the emergency department. There is not yet a sufficient level of evidence to support its routine use. In Brasil, the procedure stopped being considered an experimental technique by the Federal Council of Medicine only in 2017. The objective of the present case is to share the pioneering spirit of a Brazilian reference center with ECPR in the emergency room and to discuss the future challenges of the ECMO technique.

Heterotopic Heart Transplantation as a Left Ventricular Biological Assistance: a New Two-Stage Method Proposal.

Since Barnard's first heterotopic heart transplant in 1974, Copeland's method has been the greatest contribution to heterotopic transplants but has the drawback of donor's right ventricular atrophy. This new method proposes a modification in the anastomosis of the superior vena cava aiming to pre-serve donor's right ventricular function by decompressing the pulmonary territory and reducing the pulmonary arterial pressure, as a biological ventricular assist device. Finally, a second intervention is proposed, where a "twist" is performed to place the donor's heart in an orthotopic position after re-moval of the native heart. A pioneering research on this method received approval from the ethics committee of the Heart Institute of São Paulo. We believe that this method has the potential to im-prove quality of life in a selected group of patients.

Heterotopic heart transplantation as a left ventricular biological assistance: a new two-stage method proposal

Abstract Since Barnard's first heterotopic heart transplant in 1974, Copeland's method has been the greatest contribution to heterotopic transplants but has the drawback of donor's right ventricular atrophy. This new method proposes a modification in the anastomosis of the superior vena cava aiming to pre-serve donor's right ventricular function by decompressing the pulmonary territory and reducing the pulmonary arterial pressure, as a biological ventricular assist device. Finally, a second intervention is proposed, where a "twist" is performed to place the donor's heart in an orthotopic position after re-moval of the native heart. A pioneering research on this method received approval from the ethics committee of the Heart Institute of São Paulo. We believe that this method has the potential to im-prove quality of life in a selected group of patients.

Quadricuspid Aortic Valve: Three Cases Report and Literature Review.

Quadricuspid aortic valve (QAV) is a rare cardiac malformation. Many cases are incidentally diagnosed in aortic surgeries or autopsies and it usually appears as an isolated anomaly. The most widely classification used is the one by Hurwitz and Roberts[], which divides 7 alphabetical subtypes based on the cusps size. The aim of this report is to describe three different anatomic presentations of this rare aortic valve anomaly.

Quadricuspid aortic valve: three cases report and literature review

Abstract Quadricuspid aortic valve (QAV) is a rare cardiac malformation. Many cases are incidentally diagnosed in aortic surgeries or autopsies and it usually appears as an isolated anomaly. The most widely classification used is the one by Hurwitz and Roberts[1], which divides 7 alphabetical subtypes based on the cusps size. The aim of this report is to describe three different anatomic presentations of this rare aortic valve anomaly.

Acute myocardial infarction in a patient with active actinic rectitis bleeding: Between the sword and the wall.

A The coronary artery bypass graft (CABG) is common. Sometimes can be challenging. Here we present a 79-year-old man presented with unstable angina and simultaneous activelower gastrointestinal bleeding (hemoglobin level, 5.1 g/L) due to actinic rectitis after radiation therapy for prostate carcinoma performed 1 year previously. Coronary angiography showed marked stenosis of the left anterior descending artery. Antiplatelet aggregation therapy, such as percutaneous coronary intervention or systemic heparin therapy for coronary artery bypass, was not feasible owing to the active rectal bleeding. Therefore, off-pump CABG has performed without systemic heparin therapy and the patient recovered well. For specific cases, CABG without systemic heparin therapy can be safely performed.

Surgical Thrombectomy of Mechanical Valve Thrombosis.

BACKGROUND: The study aim was to review the authors' experience with the surgical thrombectomy of mechanical valve thrombosis at the Heart Institute of the Medical School of São Paulo University, Brazil. METHODS: Between January 1993 and March 2014, a total of 21 patients (16 females, five males; mean age 48.2 years) with mechanical valve thrombosis was treated surgically. Of these patients, 70% were in NYHA class IV, including two in cardiogenic shock; 71% of the patients had inadequate anticoagulation levels. The median period between the initial valve replacement and valve thrombosis was 105 months. Thrombosis occurred in the mitral position in 12 patients (57%) and in the aortic position in nine (43%). Clinical and surgical data were collected from hospital records. RESULTS: The major surgical finding was thrombus (57.1%), and pannus formation was found in 42.9% of patients. The mean cardiopulmonary bypass time was 90 min, and aortic cross-clamp time 63 min. Operative complications occurred in three patients (14%): two patients required revisions for bleeding and one patient needed ventricular assistance and hemodialysis. The operative mortality rate was 19% (n = 4). Two of these deaths occurred in patients who had been transferred to the operating room with cardiopulmonary resuscitation, one death was due to prolonged mechanical ventilator support and sepsis, and one was due to cardiac tamponade. The 11-year actuarial survival rate was 69.3 ± 12.9%, and the actuarial rate freedom from reintervention was 85.7 ± 13.2% during an 11-year follow up period. CONCLUSIONS: Early surgical intervention is a safe and effective treatment in patients with mechanical valve thrombosis.

Óxido nítrico inalatório no tratamento da hipertensão pulmonar persistente do recém-nascido / Inhaled nitric oxide to treat persistent pulmonary hypertension of the newborn

Objetivos: conhecer as indicações do uso de NOi, dose média utilizada e resposta ao tratamento em recém-nascidos internados em Unidade de Terapia Intensiva Neonatal. Métodos: foram analisados 62 prontuários e considerados dois grupos de recém-nascidos (RN) de acordo com o desfecho para sobrevida (n=39) ou óbito (n=23). Testes t-Student e binomial, p<0,05. Resultados: do total, 47 eram masculinos, 18 nasceram de parto normal e 44 de cesariana. Os RNs que sobreviveram tinham maior idade gestacional clínica e mais peso ao nascimento (p<0,05). Cardiopatia congênita, hipoplasia pulmonar, sepse e síndrome da membrana hialina (SMH) foram mais frequentes nos RNs que evoluíram para óbito, enquanto que a síndrome de aspiração de mecônio (SAM)estava mais presente nos RNs que sobreviveram (p<0,05). Não houve diferença significativa quanto a: asfixia perinatal, hérnia diafragmática, hipertensão pulmonar persistente neonatal (HPPN) e taquipneia transitória do recém-nascido (p>0,05). A dose inicial de NOi e a duração do tratamento foram maiores nos RNs que sobreviveram (p<0,05). A idade de início do tratamento, a dose máxima de NOi e o tempo de ventilação mecânica não apresentaram diferenças entre os grupos (p>0,05). O índice de oxigenação foi significativamente mais alto nos óbitos (p<0,05). Não foram observados efeitos colaterais. Conclusões: a terapia com NOi foi indicada principalmente na asfixia perinatal, SAM, SMH e sepse. As doses de NOi entre 15 e 30 ppm mostraram-se seguras e a diminuiçãodo índice de oxigenação sugere resposta positiva ao tratamento.

Objectives: To know the inhaled nitric oxide (iNO) use indications, the average used dose, and the reaction to treatment in newborns hospitalized at the Neonatal Intensive Care Unit. Methods: 62 medical records were analyzed and two newborn groups were considered according to the survival (n=39) or death (n=23) outcome. t-Student and binomial tests, p<0.05. Results: From the total, 47 subjects were male, 18 were born from natural childbirth, and 44 from cesarean section. The newborns that survived had a higher clinical gestational age and more weight at birth (p>0.05). Congenital heart defect, pulmonary hipoplasia, sepsis, and hyaline membrane syndrome (HMS) were more frequent in newborns that evolved to death, while the meconium aspiration syndrome (MAS) was more present in the ones that survived (p<0.05). There was no significant difference concerning: perinatal asphyxia, diaphragmatichernia, neonatal persistent pulmonary hypertension (NPPH), and newborn transient taquipneia (p>0.05). The iNO initial dose and treatment time were superior in newborns that survived (p<0.05). Age in the beginning of the treatment, maximum doses of iNO, and time of mechanical ventilation did not present significant differences between the groups (p>0.05).The oxygenation index was significantly higher in the deceased ones (p<0.05). No adverse effects were seen. Conclusions: Therapy with iNO was mainly indicated for perinatal asphyxia, MAS, HMS, and sepsis. iNO doses between 15 and 30 ppm proved to be safe, and the decrease of the oxygenation index suggests a positive reaction to the treatment.