Chagas Cardiomyopathy and Myocardial Sympathetic Denervation.

PURPOSE OF REVIEW: More than a century since its discovery, the pathogenesis of Chagas heart disease (CHD) remains incompletely understood. The role of derangements in the autonomic control of the heart in triggering malignant arrhythmia before the appearance of contractile ventricular impairment was reviewed. RECENT FINDINGS: Although previous investigations had demonstrated the anatomical and functional consequences of parasympathetic dysautonomia upon the heart rate control, only recently, coronary microvascular disturbances and sympathetic denervation at the ventricular level have been reported in patients and experimental models of CHD, exploring with nuclear medicine methods their impact on the progression of myocardial dysfunction and cardiac arrhythmias. More important than parasympathetic impaired sinus node regulation, recent evidence indicates that myocardial sympathetic denervation associated with coronary microvascular derangements is causally related to myocardial injury and arrhythmia in CHD. Additionally, 123I-MIBG imaging is a promising tool for risk stratification of progression of ventricular dysfunction and sudden death.

In-Hospital Management and Long-term Clinical Outcomes and Adherence in Patients With Acute Decompensated Heart Failure: Primary Results of the First Brazilian Registry of Heart Failure (BREATHE).

BACKGROUND: Heart failure (HF), a common cause of hospitalization, is associated with poor short-term clinical outcomes. Little is known about the long-term prognoses of patients with HF in Latin America. METHODS: BREATHE was the first nationwide prospective observational study in Brazil that included patients hospitalized due to acute heart failure (HF). Patients were included during 2 time periods: February 2011-December 2012 and June 2016-July 2018 SUGGESTION FOR REPHRASING: In-hospital management, 12-month clinical outcomes and adherence to evidence-based therapies were evaluated. RESULTS: A total of 3013 patients were enrolled at 71 centers in Brazil. At hospital admission, 83.8% had clear signs of pulmonary congestion. The main cause of decompensation was poor adherence to HF medications (27.8%). Among patients with reduced ejection fraction, concomitant use of beta-blockers, renin-angiotensin-aldosterone inhibitors and spironolactone decreased from 44.5% at hospital discharge to 35.2% at 3 months. The cumulative incidence of mortality at 12 months was 27.7%, with 24.3% readmission at 90 days and 44.4% at 12 months. CONCLUSIONS: In this large national prospective registry of patients hospitalized with acute HF, rates of mortality and readmission were higher than those reported globally. Poor adherence to evidence-based therapies was common at hospital discharge and at 12 months of follow-up.

Pentoxifylline reduces inflammation and prevents myocardial perfusion derangements in experimental chronic Chagas' cardiomyopathy.

BACKGROUND: Myocardial perfusion defect (MPD) is common in chronic Chagas cardiomyopathy (CCC) and is associated with inflammation and development of left ventricular systolic dysfunction. We tested the hypothesis that pentoxifylline (PTX) could reduce inflammation and prevent the development of MPD in a model of CCC in hamsters. METHODS AND RESULTS: We investigated with echocardiogram and rest myocardial perfusion scintigraphy at baseline (6-months after T. cruzi infection/saline) and post-treatment (after additional 2-months of PTX/saline administration), female Syrian hamsters assigned to 3 groups: T. cruzi-infected animals treated with PTX (CH + PTX) or saline (CH + SLN); and uninfected control animals (CO). At the baseline, all groups showed similar left ventricular ejection fraction (LVEF) and MPD areas. At post-treatment evaluation, there was a significant increase of MPD in CH + SLN group (0.8 ± 1.6 to 9.4 ± 9.7%), but not in CH + PTX (1.9 ± 3.0% to 2.7 ± 2.7%) that exhibited MPD area similar to CO (0.0 ± 0.0% to 0.0 ± 0.0%). The LVEF decreased in both infected groups. Histological analysis showed a reduced inflammatory infiltrate in CH + PTX group (395.7 ± 88.3 cell/mm2), as compared to CH + SLN (515.1 ± 133.0 cell/mm2), but larger than CO (193.0 ± 25.7 cell/mm2). The fibrosis and TNF-α expression was higher in both infected groups. CONCLUSIONS: The prolonged use of PTX is associated with positive effects, including prevention of MPD development and reduction of inflammation in the chronic hamster model of CCC.

Regional myocardial sympathetic denervation precedes the development of left ventricular systolic dysfunction in chronic Chagas' cardiomyopathy.

BACKGROUND: Regional myocardial sympathetic denervation is a conspicuous and early disorder in patients with chronic Chagas' cardiomyopathy (CCC), potentially associated to the progression of myocardial dysfunction OBJECTIVE: To evaluate in a longitudinal study the association between the presence and the progression of regional myocardial sympathetic denervation with the deterioration of global and segmental left ventricular dysfunction in CCC. METHODS: 18 patients with CCC were submitted at initial evaluation and after 5.5 years to rest myocardial scintigraphy with 123Iodo-metaiodobenzylguanidine and 99mTc-sestamibi and to two-dimensional echocardiography to assess myocardial sympathetic denervation, extent of fibrosis, and the left ventricular ejection fraction (LVEF) and wall motion abnormalities. RESULTS: In the follow-up evaluation, compared to the initial one, we observed a significant decrease in LVEF (56 ± 11 to 49% ± 12; P = .01) and increased summed defects scores in the myocardial innervation scintigraphy (15 ± 10 to 20 ± 9; P < .01). The presence of regional myocardial sympathetic denervation in ventricular regions of viable non-fibrotic myocardium presented an odds ratio of 4.25 for the development of new wall motion abnormalities (P = .001). CONCLUSION: Regional and global myocardial sympathetic denervation is a progressive derangement in CCC. In addition, the regional denervation is topographically associated with areas of future development of regional systolic dysfunction in patients with CCC.

Relationship between microvascular changes, autonomic denervation, and myocardial fibrosis in Chagas cardiomyopathy: Evaluation by MRI and SPECT imaging.

BACKGROUND: The relationship between microvasculopathy, autonomic denervation, and myocardial fibrosis, in Chagas cardiomyopathy is incompletely understood. The aim of this study was to explore the relative extent and anatomic distribution of myocardial hypoperfusion, autonomic denervation, and myocardial scarring using Single-Photon Emission Computerized Tomography (SPECT) imaging and Magnetic Resonance Imaging (MRI). METHODS: Thirteen patients with Chagas disease all had Iodine-123-metaiodobenzylguanidine (MIBG) SPECT, 99mTc-Sestamibi (MIBI) rest-stress SPECT, and gadolinium late enhancement MRI imaging within a 2-month interval. The anatomic location and extent of denervation, of stress-induced hypoperfusion and fibrosis, were assessed through image co-registration and quantification of abnormal tissue areas as a percent of total myocardium. RESULTS: The results showed a strong general anatomic concordance between areas of hypoperfusion, denervation, and fibrosis, suggesting that the three abnormal features may be correlated. Myocardial denervation was anatomically and quantitatively closely associated areas of stress hypoperfusion. CONCLUSION: Combined myocardial analysis of the extent and location of autonomic denervation, hypoperfusion, and scarring may allow for better understanding of the pathophysiology of Chagas cardiomyopathy. Autonomic myocardial denervation may be a more sensitive marker of cardiac involvement in Chagas Disease than finding by other imaging modalities.

Prolonged dipyridamole administration reduces myocardial perfusion defects in experimental chronic Chagas cardiomyopathy.

BACKGROUND: Myocardial perfusion defects (MPD) due to coronary microvascular dysfunction is frequent in chronic Chagas cardiomyopathy (CCC) and may be involved with development of myocardial damage. We investigated whether MPD precedes left ventricular systolic dysfunction and tested the hypothesis that prolonged use of dipyridamole (DIPY) could reduce MPD in an experimental model of CCC in hamsters. METHODS AND RESULTS: We investigated female hamsters 6-months after T. cruzi infection (baseline condition) and control animals, divided into T. cruzi-infected animals treated with DIPY (CH + DIPY) or placebo (CH + PLB); and uninfected animals treated with DIPY (CO + DIPY) or placebo (CO + PLB). The animals were submitted to echocardiogram and rest SPECT-Sestamibi-Tc99m myocardial perfusion scintigraphy. Next, the animals were treated with DIPY (4 mg/kg bid, intraperitoneal) or saline for 30 days, and reevaluated with the same imaging methods. At baseline, the CH + PLB and CH + DIPY groups showed larger areas of perfusion defect (13.2 ± 13.2% and 17.3 ± 13.2%, respectively) compared with CO + PLB and CO + DIPY (3.8 ± 2.2% e 3.5 ± 2.7%, respectively), P < .05. After treatment, we observed: reduction of perfusion defects only in the CH + DIPY group (17.3 ± 13.2% to 6.8 ± 7.6%, P = .001) and reduction of LVEF in CH + DIPY and CH + PLB groups (from 65.3 ± 9.0% to 53.6 ± 6.9% and from 69.3 ± 5.0% to 54.4 ± 8.6%, respectively, P < .001). Quantitative histology revealed greater extents of inflammation and interstitial fibrosis in both Chagas groups, compared with control group (P < .001), but no difference between Chagas groups (P > .05). CONCLUSIONS: The prolonged use of DIPY in this experimental model of CCC has reduced the rest myocardial perfusion defects, supporting the notion that those areas correspond to viable hypoperfused myocardium.

The severity of ventricular arrhythmia correlates with the extent of myocardial sympathetic denervation, but not with myocardial fibrosis extent in chronic Chagas cardiomyopathy : Chagas disease, denervation and arrhythmia.

BACKGROUND: To investigate the correlation between the extent of myocardial sympathetic denervation and fibrosis and the presence of degrees of severity of ventricular arrhythmias in chronic Chagas cardiomyopathy (CCC). METHODS: Forty-three CCC patients with left ventricular ejection fraction (LVEF) ≥ 35% were divided into three groups: SVT group-presenting Sustained Ventricular Tachycardia (SVT) (n = 15), NSVT group-exhibiting episodes of non-SVT (NSVT) on 24-h Holter monitoring (n = 11), and Control group-exhibiting neither SVT nor episodes of NSVT (n = 17). The patients underwent SPECT imaging for myocardial sympathetic innervation with 123Iodine-MIBG (MIBG) and myocardial perfusion with 99mTc-Sestamibi (MIBI) for the evaluation of regional myocardial fibrosis. RESULTS: The summed rest perfusion scores were similar in the three groups. The summed difference score between MIBG and MPI images, which evaluated the extent of denervated but viable myocardium, was significantly higher in SVT group (20.0 ± 8.0) as compared with the control group (2.0 ± 5.0, P < .0001) and with the NSVT group (11.0 ± 8.0, P < .05). CONCLUSIONS: The occurrence of ventricular arrhythmias of different degrees of severity correlates quantitatively with the extent of cardiac sympathetic denervation, but not with the extent of fibrosis, suggesting that myocardial sympathetic denervation plays a major role in triggering ventricular arrhythmia in CCC.

Pilot study testing the effect of physical training over the myocardial perfusion and quality of life in patients with primary microvascular angina.

BACKGROUND: Primary microvascular angina (PMA) is a common clinical condition associated to negative impact on quality of life (QOL) and reduced physical capacity. This study aimed at evaluating the effects of aerobic physical training (APT) on myocardial perfusion, physical capacity, and QOL in patients with PMA. METHODS: We investigated 12 patients (53.8 ± 9.7 years old; 7 women) with PMA, characterized by angina, angiographycally normal coronary arteries, and reversible perfusion defects (RPDs) detected on (99m)Tc-sestamibi-SPECT myocardial perfusion scintigraphy (MPS). At baseline and after 4 month of APT, the patients underwent MPS, cardiopulmonary test, and QOL questionnaire. Stress-rest MPS images were visually analyzed by attributing semi-quantitative scores (0 = normal; 4 = absent uptake), using a 17-segment left ventricular model. Summed stress, rest, and difference scores (SDS) were calculated. RESULTS: In comparison to the baseline, in the post-training we observed a significant increase in peak-VO2 (19.4 ± 4.8 and 22.1 ± 6.2 mL·kg(-1)·minute(-1), respectively, P = .01), reduction of SDS (10.1 ± 8.8 and 2.8 ± 4.9, P = .008), and improvement in QOL scores. CONCLUSIONS: Physical training in patients with PMA is associated with reduction of myocardial perfusion abnormalities, increasing of physical capacity, and improvement in QOL. The findings of this hypothesis-generating study suggest that APT can be a valid therapeutic option for patients with PMA.

Assessment of potential transthyretin amyloid cardiomyopathy cases in the Brazilian public health system using a machine learning model.

OBJECTIVES: To identify and describe the profile of potential transthyretin cardiac amyloidosis (ATTR-CM) cases in the Brazilian public health system (SUS), using a predictive machine learning (ML) model. METHODS: This was a retrospective descriptive database study that aimed to estimate the frequency of potential ATTR-CM cases in the Brazilian public health system using a supervised ML model, from January 2015 to December 2021. To build the model, a list of ICD-10 codes and procedures potentially related with ATTR-CM was created based on literature review and validated by experts. RESULTS: From 2015 to 2021, the ML model classified 262 hereditary ATTR-CM (hATTR-CM) and 1,581 wild-type ATTR-CM (wtATTR-CM) potential cases. Overall, the median age of hATTR-CM and wtATTR-CM patients was 66.8 and 59.9 years, respectively. The ICD-10 codes most presented as hATTR-CM and wtATTR-CM were related to heart failure and arrythmias. Regarding the therapeutic itinerary, 13% and 5% of hATTR-CM and wtATTR-CM received treatment with tafamidis meglumine, respectively, while 0% and 29% of hATTR-CM and wtATTR-CM were referred to heart transplant. CONCLUSION: Our findings may be useful to support the development of health guidelines and policies to improve diagnosis, treatment, and to cover unmet medical needs of patients with ATTR-CM in Brazil.

Impact of cardiac structure and function on exercise intolerance in Chagas cardiomyopathy: Insights from CPET and echocardiography.

INTRODUCTION: Chronic Chagas cardiomyopathy (CCC), the most severe clinical condition of Chagas disease, often leads to a reduction in functional capacity and the appearance of symptoms such as fatigue and dyspnea on exertion. However, its determinant factors remain unclear. We aimed to evaluate the peak oxygen consumption (VO2peak) in patients with CCC and identify its determining factors. METHODS: An observational study with 97 CCC patients was conducted. Patients underwent clinical examination, cardiopulmonary exercise test (CPET), and echocardiography as part of the standard clinical evaluation. Multivariate linear regression was used to identify independent clinical and echocardiographic predictors of VO2peak and percentage of predicted VO2. RESULTS: Mean age of study patients was 55.9 ± 13.4 years, median left ventricle ejection fraction (LVEF) was 40 (26-61.5) % and median VO2peak was 16.1 (12.1-20.8) ml/Kg/min. 36 patients presented preserved LVEF and 61 presented reduced LVEF. There were significant differences in almost all CPET variables (p < 0.05) between these two groups. VO2peak was associated with age, male sex, NYHA functional class, LVEF, left atrium diameter, LV diastolic diameter, E wave, LV mass index, and pulmonary artery systolic pressure (PASP). Age, male sex, LVEF, and E wave remained independently associated with VO2peak in the multivariate analysis (R2 = 0.69), furthermore, only LVEF and E wave were associated with the predicted VO2 percentage (R2 = 0.53). CONCLUSION: In patients with CCC, disease severity, male sex, LV systolic and diastolic function influence the functional capacity.

Clinical and genetic profiles of patients with hereditary and wild-type transthyretin amyloidosis: the Transthyretin Cardiac Amyloidosis Registry in the state of São Paulo, Brazil (REACT-SP).

BACKGROUND: Transthyretin amyloidosis (ATTR) is a multisystem disease caused by the deposition of fibrillar protein in organs and tissues. ATTR genotypes and phenotypes are highly heterogeneous. We present data on physical signs and symptoms, cardiac and neurological assessments and genetic profile of patients enrolled in the Transthyretin Cardiac Amyloidosis Registry of the State of São Paulo, Brazil. RESULTS: Six hundred-forty-four patients were enrolled, 505 with the variant form (ATTRv) and 139 with wild-type (ATTRwt). Eleven different mutations were detected, the most common being Val50Met (47.5%) and V142Ile (39.2%). Overall, more than half of the patients presented cardiac involvement, and the difference in this proportion between the ATTRv and ATTRwt groups was significant (43.9 vs. 89.9%; p < 0.001). The prevalence of the neurological phenotype also differed between ATTRv and ATTRwt (56.8 vs. 31.7%; p < 0.001). The mixed phenotype was found in 25.6% of the population, without a significant difference between ATTRv and ATTRwt groups. A group of patients remained asymptomatic (10.4%), with a lower proportion of asymptomatic ATTRwt patients. CONCLUSIONS: This study details the clinical and genetic spectrum of patients with ATTR in São Paulo, Brazil. This preliminary analysis highlights the considerable phenotypic heterogeneity of neurological and cardiac manifestations in patients with variant and wild-type ATTR.

Coronary microvascular dysfunction due to Chagas disease: where are we now?

INTRODUCTION: Myocardial ischemia is common in patients with chronic Chagas cardiomyopathy (CCC), but only recently clinical and experimental studies highlighted the involvement of this abnormality as contributing to the progression of myocardial damage. AREAS COVERED: Despite the absence of obstructive epicardial coronary artery disease at angiography, and limited evidence of abnormal flow regulation at the macrovascular level, remarkable functional and structural microvascular abnormalities are consistently reported by independent investigations of CCC. These derangements occur early and contribute to myocardial dysfunction. Recent research focused on reversing microvascular dysfunction as a target to positively impact the course of CCC. We conducted an extensive review of the scientific literature, aiming to summarize the role of coronary dysfunction causing myocardial ischemia in CCC, with a focus on implications for clinical management of individuals affected by this disease. EXPERT OPINION: Preclinical studies showed a clear correlation between perfusion defects and inflammation in viable but impaired dysfunctional myocardium. These findings provided further insight into the CCC complex pathophysiology and support the role of very few recent therapeutic interventions aiming to relieve myocardial ischemia. Further research is warranted to assess the efficacy of new interventions addressing reversal of microvascular ischemia and inflammation modulation and halting ventricular dysfunction progression in CCC.

Early detection of doxorubicin myocardial injury by ultrasonic tissue characterization in an experimental animal model.

UNLABELLED: In the clinical setting, the early detection of myocardial injury induced by doxorubicin (DXR) is still considered a challenge. To assess whether ultrasonic tissue characterization (UTC) can identify early DXR-related myocardial lesions and their correlation with collagen myocardial percentages, we studied 60 rats at basal status and prospectively after 2 mg/Kg/week DXR endovenous infusion. Echocardiographic examinations were conducted at baseline and at 8, 10, 12, 14 and 16 mg/Kg DXR cumulative dose. The left ventricle ejection fraction (LVEF), shortening fraction (SF), and the UTC indices: corrected coefficient of integrated backscatter (IBS) (tissue IBS intensity/ phantom IBS intensity) (CC-IBS) and the cyclic variation magnitude of this intensity curve (MCV) were measured. The variation of each parameter of study through DXR dose was expressed by the average and standard error at specific DXR dosages and those at baseline. The collagen percent (%) was calculated in six control group animals and 24 DXR group animals. CC-IBS increased (1.29±0.27 x 1.1±0.26-basal; p=0.005) and MCV decreased (9.1± 2.8 x 11.02±2.6-basal; p=0.006) from 8 mg/Kg to 16 mg/Kg DXR. LVEF presented only a slight but significant decrease (80.4±6.9% x 85.3±6.9%-basal, p=0.005) from 8 mg/Kg to 16 mg/Kg DXR. CC-IBS was 72.2% sensitive and 83.3% specific to detect collagen deposition of 4.24% (AUC=0.76). LVEF was not accurate to detect initial collagen deposition (AUC=0.54). IN CONCLUSION: UTC was able to early identify the DXR myocardial lesion when compared to LVEF, showing good accuracy to detect the initial collagen deposition in this experimental animal model.

Statins Prescriptions and Lipid Levels in a Tertiary Public Hospital. / Perfil de Prescrição de Estatinas e de Níveis Lipêmicos em Ambulatórios de Hospital Terciário Público.

BACKGROUND: The development of a new class of medications that are highly capable of reducing LDL-cholesterol renewed the interest in the characterization of familial hypercholesterolemia patients. Nevertheless, little is known about the lipid profile of patients in tertiary healthcare centers in Brazil in order to better estimate the real occurrence of familial hypercholesterolemia, with initial suspect of LDL-cholesterol levels above 190 mg/d/L. OBJECTIVES: This study evaluated the lipid profile (total cholesterol and LDL-cholesterol) in ambulatory patients from a general tertiary public hospital. METHODS: Retrospective study comparing prescriptions of statins and lipid profile results. The significance level was established in 5%. RESULTS: In one year, 9,594 individuals received statin prescriptions, of whom 51.5% were females and the mean age was 63.7±12.9 years-old (18 to 100 years-old). Thirty-two medical specialties prescribed statins. Cardiology was responsible for 43% of the total. Nearly 15% of those patients with a prescription did not have a recent total cholesterol result and 1,746 (18%) did not have a recent LDL-cholesterol measurement. The occurrence of the latter between 130 and 190 mg/dL was present in 1,643 (17.1%) individuals, and 228 (2.4%) patients had an LDL-cholesterol ≥190mg/dL among those using statins at distinct doses. Only two statins were used: simvastatin and atorvastatin. The first was prescribed in 77.6% of the prescriptions. CONCLUSION: In this cross-sectional cohort at a tertiary general hospital, statins have been widely prescribed but with little success in achieving recognized levels of control. There is probably a significant number of FH individuals in this cohort that need to be properly diagnosed in order to receive adequate treatment due to its prognostic implications.

FUNDAMENTO: O surgimento de nova classe de medicamentos com elevada capacidade de reduzir o LDL-colesterol (LDL-c) renovou o interesse na caracterização da hipercolesterolemia familiar (HF). Pouco se conhece do perfil lipídico de pacientes em atendimento terciário em nosso meio para caracterizar a real ocorrência de HF, que começa a ser suspeitada com níveis de LDL-c acima de 190mg/dL. OBJETIVOS: O estudo avaliou o perfil lipídico (colesterol total [CT] e LDL-c) de pacientes de hospital público terciário. MÉTODOS: Estudo retrospectivo de avaliação de prescrições de estatinas e resultados dos lipídios. O nível de significância foi estabelecido em 5%. RESULTADOS: Em 1 ano, 9.594 indivíduos receberam prescrição ambulatorial de estatinas, 51,5% do gênero feminino, idade média de 63,7±12,9 anos (18 a 100 anos). Trinta e duas especialidades prescreveram estatinas, sendo a cardiologia responsável por 43%. Cerca de 15% das prescrições não tinham dosagem recente de CT, e 1.746 (18,0%) não apresentavam resultado recente de LDL-c. A ocorrência de LDL-c > 130mg/dL e < 190mg/dL ocorreu em 1.643 (17,1%) casos, e 228 (2,4%) apresentaram LDL-c ≥ 190mg/dL dentre os que utilizavam estatinas nas diversas doses. Apenas duas estatinas foram utilizadas: sinvastatina e atorvastatina, e a primeira foi prescrita em 77,6% das receitas. CONCLUSÃO: Nesta coorte transversal de hospital terciário, foi possível verificar que a prescrição de estatinas é disseminada, mas que a obtenção de metas adequadas de CT e LDL-c não é atingida em grande percentual, e que há, possivelmente, significativo contingente de portadores de HF que necessitariam ser investigados por suas implicações prognósticas.

Prospective study of ventricular function and myocardial deformation related to survival in acute Chagas disease: an experimental animal model.

Chagas disease (CD) has been changing from an endemic Latino-American disease to a condition found outside endemic regions, due to migratory movements. Although often subclinical, its acute phase can be lethal. This study aimed to assess survival during the acute phase of CD and its relationship with ventricular function in an experimental model. To this end, 30 Syrian hamsters were inoculated with Trypanosoma cruzi (IG) and other 15 animals received saline solution (CG). Groups were monitored daily and submitted to echocardiography in two moments: before the challenge and 15 days post-infection. Left ventricular ejection fraction (LVEF) and global longitudinal myocardial strain (GLS) of the LV were measured. The IG was divided into groups of animals with and without clinical signs of disease. ANOVA for mixed models was used to compare ventricular function parameters. Survival analysis was studied using Kaplan-Meier curves and the log-rank test. The follow-up lasted 60 days. LVEF in IG was reduced through time (53.80 to 43.55%) compared to CG (57.86 to 59.73%) (p=0.002). There was also a reduction of GLS (-18.97% to -12.44%) in the IG compared to CG (p=0.012). Twelve animals from IG died compared to one animal from CG. Eleven out of the 12 animals from the IG group died before presenting with clinical signs of infection. Survival was reduced in the IG compared to CG over time (p=0.02). The reduced survival during the acute phase of this experimental model of Chagas disease was related to the significant reduction of LV function. The mortality rate in the IG was higher in the group presenting with clinical signs of infection.

Revisiting heart failure assessment based on objective measures in NYHA functional classes I and II.

OBJECTIVE: New York Heart Association (NYHA) functional class plays a central role in heart failure (HF) assessment but might be unreliable in mild presentations. We compared objective measures of HF functional evaluation between patients classified as NYHA I and II in the Rede Brasileira de Estudos em Insuficiência Cardíaca (ReBIC)-1 Trial. METHODS: The ReBIC-1 Trial included outpatients with stable HF with reduced ejection fraction. All patients had simultaneous protocol-defined assessment of NYHA class, 6 min walk test (6MWT), N-terminal pro-brain natriuretic peptide (NT-proBNP) levels and patient's self-perception of dyspnoea using a Visual Analogue Scale (VAS, range 0-100). RESULTS: Of 188 included patients with HF, 122 (65%) were classified as NYHA I and 66 (35%) as NYHA II at baseline. Although NYHA class I patients had lower dyspnoea VAS Scores (median 16 (IQR, 4-30) for class I vs 27.5 (11-49) for class II, p=0.001), overlap between classes was substantial (density overlap=60%). A similar profile was observed for NT-proBNP levels (620 pg/mL (248-1333) vs 778 (421-1737), p=0.015; overlap=78%) and for 6MWT distance (400 m (330-466) vs 351 m (286-408), p=0.028; overlap=64%). Among NYHA class I patients, 19%-34% had one marker of HF severity (VAS Score >30 points, 6MWT <300 m or NT-proBNP levels >1000 pg/mL) and 6%-10% had two of them. Temporal change in functional class was not accompanied by variation on dyspnoea VAS (p=0.14). CONCLUSIONS: Most patients classified as NYHA classes I and II had similar self-perception of their limitation, objective physical capabilities and levels of natriuretic peptides. These results suggest the NYHA classification poorly discriminates patients with mild HF.

Implications for Clinical Practice from a Multicenter Survey of Heart Failure Management Centers.

OBJECTIVES: This observational, cross-sectional study based aimed to test whether heart failure (HF)-disease management program (DMP) components are influencing care and clinical decision-making in Brazil. METHODS: The survey respondents were cardiologists recommended by experts in the field and invited to participate in the survey via printed form or email. The survey consisted of 29 questions addressing site demographics, public versus private infrastructure, HF baseline data of patients, clinical management of HF, performance indicators, and perceptions about HF treatment. RESULTS: Data were obtained from 98 centers (58% public and 42% private practice) distributed across Brazil. Public HF-DMPs compared to private HF-DMP were associated with a higher percentage of HF-DMP-dedicated services (79% vs 24%; OR: 12, 95% CI: 94-34), multidisciplinary HF (MHF)-DMP [84% vs 65%; OR: 3; 95% CI: 1-8), HF educational programs (49% vs 18%; OR: 4; 95% CI: 1-2), written instructions before hospital discharge (83% vs 76%; OR: 1; 95% CI: 0-5), rehabilitation (69% vs 39%; OR: 3; 95% CI: 1-9), monitoring (44% vs 29%; OR: 2; 95% CI: 1-5), guideline-directed medical therapy-HF use (94% vs 85%; OR: 3; 95% CI: 0-15), and less B-type natriuretic peptide (BNP) dosage (73% vs 88%; OR: 3; 95% CI: 1-9), and key performance indicators (37% vs 60%; OR: 3; 95% CI: 1-7). In comparison to non- MHF-DMP, MHF-DMP was associated with more educational initiatives (42% vs 6%; OR: 12; 95% CI: 1-97), written instructions (83% vs 68%; OR: 2: 95% CI: 1-7), rehabilitation (69% vs 17%; OR: 11; 95% CI: 3-44), monitoring (47% vs 6%; OR: 14; 95% CI: 2-115), GDMT-HF (92% vs 83%; OR: 3; 95% CI: 0-15). In addition, there were less use of BNP as a biomarker (70% vs 84%; OR: 2; 95% CI: 1-8) and key performance indicators (35% vs 51%; OR: 2; 95% CI: 91,6) in the non-MHF group. Physicians considered changing or introducing new medications mostly when patients were hospitalized or when observing worsening disease and/or symptoms. Adherence to drug treatment and non-drug treatment factors were the greatest medical problems associated with HF treatment. CONCLUSION: HF-DMPs are highly heterogeneous. New strategies for HF care should consider the present study highlights and clinical decision-making processes to improve HF patient care.

Emerging Topics in Heart Failure: New Paradigms in Cardiac Amyloidosis. / Tópicos Emergentes em Insuficiência Cardíaca: Novos Paradigmas na Amiloidose Cardíaca.

Recent evidence suggests cardiac amyloidosis (CA) is a mostly underdiagnosed condition, particularly in the transthyretin-mediated form, and is a frequent cause of heart failure with preserved ejection fraction (HFpEF) in the elderly. New paradigms about CA also involve the development of disease-modifying specific therapies. This article summarizes these new concepts.

Evidências recentes sugerem que a amiloidose cardíaca é uma doença amplamente subdiagnosticada, particularmente na sua forma ligada à transtirretina, podendo ser uma causa comum de insuficiência cardíaca com fração de ejeção preservada (ICFEP) no idoso. Os novos paradigmas sobre a doença incluem o desenvolvimento de novas terapias específicas que modificam a história natural da doença. Este artigo traz uma síntese destes novos conceitos.

High-dose versus low-dose angiotensin converting enzyme inhibitors in heart failure: systematic review and meta-analysis.

OBJECTIVE: To systematically review evidence comparing the effect of low-dose versus high-dose ACE inhibitors (ACEIs) on all-cause and cardiovascular mortality and hospitalisation, functional capacity and side effects in patients with heart failure (HF). METHODS: We searched PubMed, Embase, Cochrane CENTRAL and LILACS up to January 2019. We included randomised controlled trials (RCTs) comparing low-dose versus high-dose ACEIs in adults with HF with reduced left ventricular ejection fraction (HFrEF). Study selection and data extraction were performed by two independent reviewers. Risk of bias was assessed with RoB 2.0, and quality of evidence with Grading of Recommendations Assessment, Development and Evaluation (GRADE). We conducted random effects meta-analysis and trial sequential analysis. RESULTS: We included eight RCTs (5829 patients with HF). In comparison with low-dose ACEIs, high-dose ACEIs showed a non-significant effect on all-cause mortality (8 RCTs, n=5828, relative risk (RR) 0.95, 95% CI 0.88 to 1.02; moderate quality of evidence), cardiovascular mortality (6 RCTs, n=4048, RR 0.93, 95% CI 0.85 to 1.01; moderate quality of evidence), all-cause hospitalisation (5 RCTs, n=5394, RR 0.95, 95% CI 0.82 to 1.10; moderate quality of evidence) and cardiovascular hospitalisation (4 RCTs, n=5242, RR 0.98, 95% CI 0.83 to 1.17; low quality of evidence). High-dose ACEI increased functional capacity (4 studies, n=555, standardised mean difference 0.38, 95% CI 0.20 to 0.55; low quality of evidence) and the risk of hypotension (4 RCTs, n=3783, RR 1.64, 95% CI 1.30 to 2.05; moderate quality of evidence). High-dose ACEI had no effect on dizziness (3 RCTs, n=4994, RR 1.37, 95% CI 0.97 to 1.93; low quality of evidence), but decreased the risk of cough (4 RCTs, n=5146, RR 0.85, 95% CI 0.73 to 0.98; moderate quality of evidence). CONCLUSIONS: The magnitude of benefit of using high dose versus low to intermediate doses of ACEIs might be less than traditionally suggested in clinical guidelines. These findings might help clinicians address the complex task of HF management in a more rational and timely fashion, saving efforts to implement strategies with the greatest net clinical benefit.

Should we use ferritin in the diagnostic criteria of iron deficiency in heart failure patients?

BACKGROUND AND AIMS: Iron deficiency (ID) is a common comorbidity in patients with chronic heart failure (HF) and is associated with worse prognosis. We aimed at comparing the currently European Society of Cardiology (ESC) criterion for diagnosis of ID (ferritin < 100 µg/L or ferritin 100-299 µg/L with transferrin saturation [TSAT] < 20%) with either isolated low TSAT or isolated low ferritin on survival, in a cohort of HF patients. METHODS: This was an observational prospective study, investigating ambulatory patients with HF and reduced ejection fraction (n = 108). All patients were assessed for clinical aspects and iron indexes. The primary endpoint was all-cause death. RESULTS: Abnormal iron status was observed in 50 (46%) of patients. During the median follow-up time of 857.5 [647-899] days, 31 patients died (29%). In univariate analyses ESC-criterion (p = 0.022) and isolated TSAT <20% (p = 0.002), but not isolated ferritin <100 µg/L (p = 0.439), were significantly related to an increased risk of all-cause death. However, in multivariate analyses only TSAT <20% (HR = 2.3; [95% CI: 1.11-4.85]; p = 0.026) was independently related to all-cause mortality. CONCLUSIONS: Our results indicated that diagnosis of ID based on isolated TSAT <20% identifies HF patients with worse prognosis, while ferritin was not associated with mortality risk, suggesting that ferritin should not be taken into account for evaluation of clinical impact of ID in HF patients.