Transcriptomic profiling of cardiac tissues from SARS-CoV-2 patients identifies DNA damage.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is known to present with pulmonary and extra-pulmonary organ complications. In comparison with the 2009 pandemic (pH1N1), SARS-CoV-2 infection is likely to lead to more severe disease, with multi-organ effects, including cardiovascular disease. SARS-CoV-2 has been associated with acute and long-term cardiovascular disease, but the molecular changes that govern this remain unknown. In this study, we investigated the host transcriptome landscape of cardiac tissues collected at rapid autopsy from seven SARS-CoV-2, two pH1N1, and six control patients using targeted spatial transcriptomics approaches. Although SARS-CoV-2 was not detected in cardiac tissue, host transcriptomics showed upregulation of genes associated with DNA damage and repair, heat shock, and M1-like macrophage infiltration in the cardiac tissues of COVID-19 patients. The DNA damage present in the SARS-CoV-2 patient samples, were further confirmed by γ-H2Ax immunohistochemistry. In comparison, pH1N1 showed upregulation of interferon-stimulated genes, in particular interferon and complement pathways, when compared with COVID-19 patients. These data demonstrate the emergence of distinct transcriptomic profiles in cardiac tissues of SARS-CoV-2 and pH1N1 influenza infection supporting the need for a greater understanding of the effects on extra-pulmonary organs, including the cardiovascular system of COVID-19 patients, to delineate the immunopathobiology of SARS-CoV-2 infection, and long term impact on health.

Cardiogenic shock treated with temporary mechanical circulatory support in Brazil: The effect of learning curve.

AIMS: Treatment with mechanical circulatory support (MCS) has been proposed to mitigate mortality in cardiogenic shock (CS). However, there is a lack of data on MCS programs implementation and the effect of the learning curve on its outcomes in limited resources countries such as Brazil. METHODS: Prospective cohort of patients with CS admitted in four tertiary-care centers treated with Impella CP or veno-arterial extracorporeal membrane oxygenation (VA-ECMO). Clinical outcomes were peri-procedural complications, short-term mortality rate, and the centers' learning curve. The cohort was divided into two periods: from April 2017 to July 2018 (n = 24), and from August 2018 to December 2020 (n = 25). RESULTS: The study enrolled 49 patients [age 59 (43-63) years; 34 (70%) males]. The most common causes for CS were acute myocardial infarction in 22 (45%) and acute decompensation of chronic heart failure in 10 (20%). VA-ECMO was employed in 35 (71%) and Impella CP in 14 (29%) of patients. Overall complications occurred in 37 (76%) of patients, where major bleeding in 19 (38%) was the most common. The overall mortality rate was 61%, but it was lower in the second period (40%) in comparison to the first period (83%), p = 0.002. The learning curve analysis showed a decrease in the mortality rate after 40 consecutive cases. CONCLUSIONS: Implementation of a temporary MCS program for refractory CS in a limited resource country is feasible. The learning curve effect might have played a role on survival rate since high morbimortality has decreased within time reaching optimal results by the end of the study.

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.

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.

Use of sacubitril/valsartan in non-compaction cardiomyopathy: a case report.

The use of sacubitril/valsartan significantly reduces death or hospitalization in patients with ejection fraction < 40%. There is no study evaluating this drug effects in non-compaction cardiomyopathy (NCCM) individuals. The aim of this article is to report a case of a patient with NCCM initially refractory to gold standard treatment and afterwards treated with sacubitril/valsartan and its improvements. This is a case report of a 48-year-old woman, presenting with NCCM heart failure, who had received standard guideline-directed medical therapy for 18 months without any improvement in clinical and echocardiographic parameters. After that period, sacubitril/valsartan was initiated. After 18 months of refractory usage of guideline-directed medical therapy, sacubitril/valsartan was started, and significant change in functional class (III to I) and important ventricular remodelling were achieved with an improvement of 29% in the ejection fraction, reduction of 7 mm in ventricular diastolic diameter, and mild to none mitral valve functional regurgitation. In this case report, sacubitril/valsartan use was associated with improvement of echocardiographic and clinical parameters in a patient with NCCM.

Short-term diuretic withdrawal in stable outpatients with mild heart failure and no fluid retention receiving optimal therapy: a double-blind, multicentre, randomized trial.

AIMS: Although loop diuretics are widely used to treat heart failure (HF), there is scarce contemporary data to guide diuretic adjustments in the outpatient setting. METHODS AND RESULTS: In a prospective, randomized and double-blind protocol, we tested the safety and tolerability of withdrawing low-dose furosemide in stable HF outpatients at 11 HF clinics in Brazil. The trial had two blindly adjudicated co-primary outcomes: (i) symptoms assessment quantified as the area under the curve (AUC) of a dyspnoea score on a visual-analogue scale evaluated at 4 time-points (baseline, Day 15, Day 45, and Day 90) and (ii) the proportion of patients maintained without diuretic reuse during follow-up. We enrolled 188 patients (25% females; 59 ± 13 years old; left ventricular ejection fraction = 32 ± 8%) that were randomized to furosemide withdrawal (n = 95) or maintenance (n = 93). For the first co-primary endpoint, no significant difference in patients' assessment of dyspnoea was observed in the comparison of furosemide withdrawal with continuous administration [median AUC 1875 (interquartile range, IQR 383-3360) and 1541 (IQR 474-3124), respectively; P = 0.94]. For the second co-primary endpoint, 70 patients (75.3%) in the withdrawal group and 77 patients (83.7%) in the maintenance group were free of furosemide reuse during follow-up (odds ratio for additional furosemide use with withdrawal 1.69, 95% confidence interval 0.82-3.49; P = 0.16). Heart failure-related events (hospitalizations, emergency room visits, and deaths) were infrequent and similar between groups (P = 1.0). CONCLUSIONS: Diuretic withdrawal did not result in neither increased self-perception of dyspnoea nor increased need of furosemide reuse. Diuretic discontinuation may deserve consideration in stable outpatients with no signs of fluid retention receiving optimal medical therapy. CLINICALTRIALS.GOV IDENTIFIER: NCT02689180.

Rational and design of a randomized, double-blind, multicenter trial to evaluate the safety and tolerability of furosemide withdrawal in stable chronic outpatients with heart failure: The ReBIC-1 trial.

AIMS: Furosemide is commonly prescribed for symptom relief in heart failure (HF) patients. Although few data support the continuous use of loop diuretics in apparently euvolemic HF patients with mild symptoms, there is concern about safety of diuretic withdrawal in these patients. The ReBIC-1 trial was designed to evaluate the safety and tolerability of withdrawing furosemide in stable, euvolemic, chronic HF outpatients. This multicenter initiative is part of the Brazilian Research Network in Heart Failure (ReBIC) created to develop clinical studies in HF and composed predominantly by university tertiary care hospitals. METHODS: The ReBIC-1 trial is currently enrolling HF patients in NYHA functional class I-II, left ventricular ejection fraction ≤45%, without a HF-related hospital admission within the last 6 months, receiving a stable dose of furosemide (40 or 80 mg per day) for at least 6 months. Eligible patients will be randomized to maintain or withdraw furosemide in a double-blinded protocol. The trial has two co-primary outcomes: (1) dyspnea assessment using a visual-analogue scale evaluated at 4 time points and (2) the proportion of patients maintained without diuretics during the follow-up period. Total sample size was calculated to be 220 patients. Enrolled patients will be followed up to 90 days after randomization, and diuretic will be restarted if clinical deterioration or signs of congestion are detected. Pre-defined sub-group analysis based on NT-proBNP levels at baseline is planned. PERSPECTIVE: Evidence-based strategies aiming to simplify HF pharmacotherapy are needed in clinical practice. The ReBIC-1 trial will determine the safety of withdrawing furosemide in stable chronic HF patients.

Effects of the recombinant form of the natural human B-type natriuretic peptide and levosimendan on pulmonary hyperventilation and chemosensivity in heart failure.

BACKGROUND: The origin of dyspnea in chronic heart failure (HF) is multifactorial, and excessive ventilation is thought to play a role in inducing this symptom. Chemosensivity is augmented in HF, correlates with increased pulmonary ventilation (VE), and is an adverse prognostic marker. Despite increased blood levels of natriuretic peptides in clinical conditions associated with dyspnea, their effect on pulmonary VE and chemoreceptor activity remains unexplored. METHODS: We tested in a prospective, placebo-controlled, three-way cross-over, double-blind randomized study the effects of the recombinant form of the natural human B-type natriuretic peptide (R-BNP) in comparison with placebo and levosimendan on chemoreflex sensitivity at rest, as well as their effects on pulmonary VE, systemic blood pressure, heart rate and sympathetic serum activity both at rest and during exercise. RESULTS: Eleven stable chronic HF patients were randomized to sessions of 6-min treadmill-walking tests during placebo, or levosimendan or R-BNP intravenous infusion in the following conditions: room air, hypoxia, and hypercapnia. R-BNP administration determined higher pulmonary ventilatory response at rest and during exercise (P < 0.001) consequent to a boost of respiratory rate (P < 0.001) under room air and hypoxia conditions. Norepinephrine blood levels increased from rest to exercise in all conditions without differences among placebo, levosimendan, and R-BNP effects. BNP blood levels remained unchanged. CONCLUSIONS: The novelty of the present findings is that R-BNP infusion in HF patients can boost pulmonary ventilatory response at rest and during exercise.

Quimiossensibilidade durante exercício na insuficiência cardíaca: respostas ventilatórias, cronotrópicas e neurohormonais / Exercise chemosensitivity in heart failure: ventilatory, chronotropic and neurohormonal responses / Quimiosensibilidad durante ejercicio en la insuficiencia cardíaca: respuestas ventilatorias, cronotrópicas y neurohormonales

FUNDAMENTO: Insuficiência cardíaca (IC) está associada com aumento da quimio-sensibilidade periférica e central em repouso, que pode estar correlacionada com um aumento na resposta ventilatória durante exercício. Entretanto, SUS sensibilidade na IC durante o exercício ainda não foi reportada. OBJETIVO: Testar se o estímulo dos quimiorreceptores centrais e periféricos em pacientes com IC pode modular respostas ventilatórias, cronotrópicas e neurohormonais durante exercício submáximo. MÉTODOS: Investigamos a quimio-sensibilidade central e periférica em 15 pacientes com insuficiência cardíaca (IC) e 7 controles normais (C), comparando a resposta durante 3 testes de caminhada de 6 minutos (TC6M), realizado em esteira ergométrica com: ar ambiente, em hipóxia e em hipercapnia (em ordem randômica). RESULTADOS: FR em ar ambiente nos grupos C e IC foi 17±2 e 22±2 (p<,0001); em hipóxia, foi 17±1 e 23±2 (p<,02); com CO25 por cento foi 20±2 e 22±5 (p<,02). Volume tidal (VT) ou corrente em ar ambiente foi 1,25±0,17 e 1,08±0,19 (p<,01); em hipóxia 1,65±0,34 e 1,2±0,2(p<,0001); com CO25 por cento 1,55±0,46 e 1,29±0,39 (p<,0001). Em repouso, o aumento na IC foi maior para VE (C 33±40 por cento, IC 62±94 por cento, p<,01), FC(C 7±10 por cento, IC 10±10 por cento, p<0,05) em repouso. Durante a hipóxia, o aumento durante o exercício na IC foi maior para FR (C 1±4, IC 11±6,p<,05), FC (C 12±2, IC 14±3, p<,05), VE/VO2 (C -4±18 por cento, IC 24±21 por cento, p<,01), FC/VO2 (C -26±11 por cento, IC 11±5 por cento, p<,01), VE/DC (C 36±10 por cento, 46±14, p<,05 por cento ) and FC/DC (C 18±8 por cento, HF 29±11, p<,01). Durante exercício em hipóxia no grupo IC, o NO diminuiu e os níveis de IL-6 e aldosterona aumentaram. Os níveis neurohormonais permaneceram inalterados no grupo C. CONCLUSÃO: A quimio-sensibilidade central e a periférica durante o exercício estão aumentadas na IC e podem modular padrões respiratórios, cronotrópicos cardíacos e atividade neurohormonal durante exercício.

BACKGROUND: Heart failure (HF) is associated with resting increased peripheral and central chemosensitivity which may correlate with an increased ventilatory response to exercise. However, its sensitivity in HF during exercise was never really reported. OBJECTIVE: We tested if stimulation of central and peripheral chemoreceptors in HF patients could modulate ventilatory, chronotropic, and neurohormonal response during submaximal exercise. METHODS: We investigated central and peripheral chemosensitivity in 15 HF and 7 control (C) comparing response through three 6 minute walking tests conducted in a treadmill with : room air, hypoxia, and hypercapnia (in a randomic order). RESULTS: RR at room air C and HF was 17±2 and 22±2 (p<.0001); at hypoxia 17±1 and 23±2 (p<.02); at CO25 percent was 20±2 and 22±5 (p<.02). Tidal volume (TV) at room air was 1.25±0.17 and 1.08±0.19 (p<.01); at hypoxia 1.65±0.34 and 1.2±0.2 (p<.0001); at CO25 percent 1.55±0.46 and 1.29±0.39 (p<.0001). At rest the increment in HF was higher for VE (C 33±40 percent, HF 62±94 percent, p<.01), HR(C 7±10 percent, HF 10±10 percent, p<0.05) at rest. During hypoxia exercise increment in HF was higher for RR (C 1±4, HF 11±6,p<.05), HR (C 12±2, HF 14±3, p<.05), VE/VO2 (C -4±18 percent, HF 24±21 percent, p<.01), HR/VO2 (C -26±11 percent, HF 11±5 percent, p<.01), VE/WD (C 36±10 percent, 46±14, p<.05 percent) and HR/WD (C 18±8 percent, HF 29±11, p<.01). During HF hypoxia exercise NO reduced, and IL-6, aldosterone levels increased. Neurohormonal levels unchanged in C. CONCLUSION: Exercise peripheral and central chemosensitivity are increased in HF and may modulate respiratory pattern, cardiac chronotropic, and neurohormonal activity during exercise.

FUNDAMENTO: La insuficiencia cardíaca (IC) está asociada con aumento de la quimiosensibilidad periférica y central en reposo, que puede estar correlacionada con un aumento en la respuesta ventilatoria durante ejercicio. Mientras tanto, SUS sensibilidad en la IC durante el ejercicio aun no fue reportada. OBJETIVO: Verificar si el estímulo de los quimiorreceptores centrales y periféricos en pacientes con IC puede modular respuestas ventilatorias, cronotrópicas y neurohormonales durante ejercicio submáximo. MÉTODOS: Investigamos la quimiosensibilidad central y periférica en 15 pacientes con insuficiencia cardíaca (IC) y 7 controles normales (C), comparando la respuesta durante 3 tests de caminata de 6 minutos (TC6M), realizado en cinta ergométrica con: aire ambiente, en hipoxia y en hipercapnia (en orden randómico). RESULTADOS: FR en aire ambiente en los grupos C y IC fue 17±2 y 22±2 (p<,0001); en hipoxia, fue 17±1 y 23±2 (p<.02); con CO25 por ciento fue 20±2 y 22±5 (p<,02). Volumen tidal (VT) o corriente en aire ambiente fue 1,25±0,17 y 1,08±0,19 (p<,01); en hipoxia 1,65±0,34 y 1,2±0,2 (p<,0001); con CO25 por ciento 1,55±0,46 y 1,29±0,39 (p<,0001). En reposo, el aumento en la IC fue mayor para VI (C 33±40 por ciento, IC 62±94 por ciento, p<,01), FC(C 7±10 por ciento, IC 10±10 por ciento, p<0,05) en reposo. Durante la hipoxia, el aumento durante el ejercicio en la IC fue mayor para FR (C 1±4, IC 11±6, p<.05), FC (C 12±2, IC 14±3, p<.05), VI/VO2 (C -4±18 por ciento, IC 24±21 por ciento, p<.01), FC/VO2 (C -26±11 por ciento, IC 11±5 por ciento, p<.01), VI/DC (C 36±10 por ciento, 46±14, p<.05 por ciento) y FC/DC (C 18±8 por ciento, HF 29±11, p<.01). Durante ejercicio en hipoxia en el grupo IC, el NO disminuyó y los niveles de IL-6 y aldosterona aumentaron. Los niveles neurohormonales permanecieron inalterados en el grupo C. CONCLUSIÓN: La quimiosensibilidad central y la periférica durante el ejercicio están aumentadas en la IC y pueden modular estándares respiratorios, cronotrópicos cardíacos y actividad neurohormonal durante ejercicio.

Exercise chemosensitivity in heart failure: ventilatory, chronotropic and neurohormonal responses.

BACKGROUND: Heart failure (HF) is associated with resting increased peripheral and central chemosensitivity which may correlate with an increased ventilatory response to exercise. However, its sensitivity in HF during exercise was never really reported. OBJECTIVE: We tested if stimulation of central and peripheral chemoreceptors in HF patients could modulate ventilatory, chronotropic, and neurohormonal response during submaximal exercise. METHODS: We investigated central and peripheral chemosensitivity in 15 HF and 7 control (C) comparing response through three 6 minute walking tests conducted in a treadmill with : room air, hypoxia, and hypercapnia (in a randomic order). RESULTS: RR at room air C and HF was 17±2 and 22±2 (p<.0001); at hypoxia 17±1 and 23±2 (p<.02); at CO25% was 20±2 and 22±5 (p<.02). Tidal volume (TV) at room air was 1.25±0.17 and 1.08±0.19 (p<.01); at hypoxia 1.65±0.34 and 1.2±0.2 (p<.0001); at CO25% 1.55±0.46 and 1.29±0.39 (p<.0001). At rest the increment in HF was higher for VE (C 33±40%, HF 62±94%, p<.01), HR(C 7±10%, HF 10±10%, p<0.05) at rest. During hypoxia exercise increment in HF was higher for RR (C 1±4, HF 11±6,p<.05), HR (C 12±2, HF 14±3, p<.05), VE/VO2 (C -4±18%, HF 24±21%, p<.01), HR/VO2 (C -26±11%, HF 11±5%, p<.01), VE/WD (C 36±10%, 46±14, p<.05%) and HR/WD (C 18±8%, HF 29±11, p<.01). During HF hypoxia exercise NO reduced, and IL-6, aldosterone levels increased. Neurohormonal levels unchanged in C. CONCLUSION: Exercise peripheral and central chemosensitivity are increased in HF and may modulate respiratory pattern, cardiac chronotropic, and neurohormonal activity during exercise.