Induction therapy in heart transplantation: A systematic review and network meta-analysis for developing evidence-based recommendations.

INTRODUCTION: Induction therapy (IT) utility in heart transplantation (HT) remains contested. Commissioned by a clinical-practice guidelines panel to evaluate the effectiveness and safety of IT in adult HT patients, we conducted this systematic review and network meta-analysis (NMA). METHODS: We searched for studies from January 2000 to October 2022, reporting on the use of any IT agent in adult HT patients. Based on patient-important outcomes, we performed frequentist NMAs separately for RCTs and observational studies with adjusted analyses, and assessed the certainty of evidence using the GRADE framework. RESULTS: From 5156 publications identified, we included 7 RCTs and 12 observational studies, and report on two contemporarily-used IT agents-basiliximab and rATG. The RCTs provide only very low certainty evidence and was uninformative of the effect of the two agents versus no IT or one another. With low certainty in the evidence from observational studies, basiliximab may increase 30-day (OR 1.13; 95% CI 1.06-1.20) and 1-year (OR 1.11; 95% CI 1.02-1.22) mortality compared to no IT. With low certainty from observational studies, rATG may decrease 5-year cardiac allograft vasculopathy (OR .82; 95% CI .74-.90) compared to no IT, as well as 30-day (OR .85; 95% CI .80-.92), 1-year (OR .87; 95% CI .79-.96), and overall (HR .84; 95% CI .76-.93) mortality compared to basiliximab. CONCLUSION: With low and very low certainty in the synthetized evidence, these NMAs suggest possible superiority of rATG compared to basiliximab, but do not provide compelling evidence for the routine use of these agents in HT recipients.

Use of induction therapy post-heart transplantation: Clinical practice recommendations based on systematic review and network meta-analysis of evidence.

BACKGROUND: The use of induction therapy (IT) agents in the early post-heart transplant period remains controversial. The following recommendations aim to provide guidance on the use of IT agents, including Basiliximab and Thymoglobulin, as part of routine care in heart transplantation (HTx). METHODS: We recruited an international, multidisciplinary panel of 15 stakeholders, including patient partners, transplant cardiologists and surgeons, nurse practitioners, pharmacists, and methodologists. We commissioned a systematic review on benefits and harms of IT on patient-important outcomes, and another on patients' values and preferences to inform our recommendations. We used the GRADE framework to summarize our findings, rate certainty in the evidence, and develop recommendations. The panel considered the balance between benefits and harms, certainty in the evidence, and patient's values and preferences, to make recommendations for or against the routine post-operative use of Thymoglobulin or Basiliximab. RESULTS: The panel made recommendations on three major clinical problems in HTx: (1) We suggest against the routine post-operative use of Basiliximab compared to no IT, (2) we suggest against the routine use of Thymoglobulin compared to no IT, and (3) for those patients for whom IT is deemed desirable, we suggest for the use of Thymoglobulin as compared to Basiliximab. CONCLUSION: This report highlights gaps in current knowledge and provides directions for clinical research in the future to better understand the clinical utility of IT agents in the early post heart transplant period, leading to improved management and care.

New Mechanisms to Prevent Heart Failure with Preserved Ejection Fraction Using Glucagon-like Peptide-1 Receptor Agonism (GLP-1 RA) in Metabolic Syndrome and in Type 2 Diabetes: A Review.

This review examines the impact of obesity on the pathophysiology of heart failure with preserved ejection fraction (HFpEF) and focuses on novel mechanisms for HFpEF prevention using a glucagon-like peptide-1 receptor agonism (GLP-1 RA). Obesity can lead to HFpEF through various mechanisms, including low-grade systemic inflammation, adipocyte dysfunction, accumulation of visceral adipose tissue, and increased pericardial/epicardial adipose tissue (contributing to an increase in myocardial fat content and interstitial fibrosis). Glucagon-like peptide 1 (GLP-1) is an incretin hormone that is released from the enteroendocrine L-cells in the gut. GLP-1 reduces blood glucose levels by stimulating insulin synthesis, suppressing islet α-cell function, and promoting the proliferation and differentiation of ß-cells. GLP-1 regulates gastric emptying and appetite, and GLP-1 RA is currently indicated for treating type 2 diabetes (T2D), obesity, and metabolic syndrome (MS). Recent evidence indicates that GLP-1 RA may play a significant role in preventing HFpEF in patients with obesity, MS, or obese T2D. This effect may be due to activating cardioprotective mechanisms (the endogenous counter-regulatory renin angiotensin system and the AMPK/mTOR pathway) and by inhibiting deleterious remodeling mechanisms (the PKA/RhoA/ROCK pathway, aldosterone levels, and microinflammation). However, there is still a need for further research to validate the impact of these mechanisms on humans.

[Cardiotoxicity of anticancer therapies. Towards the implementation of cardio-oncology units]. / Cardiotoxicidad inducida por tratamientos oncológicos. Fundamentos para la implementación de equipos de Cardio-Oncología.

Recently, we have witnessed major improvements in cancer treatment. Early diagnosis and development of new therapies have reduced cancer-related mortality. However, these new therapies, along with greater patient survival, are associated with an increase in untoward effects, particularly in the cardiovascular system. Although cardiotoxicity induced by oncologic treatments affects predominantly the myocardium, it can also involve other structures of the cardiovascular system, becoming one of the main causes of morbidity and mortality in those who survive cancer. The main objective of cardio-oncology is to achieve the maximum benefits of oncologic treatments while minimizing their deleterious cardiovascular effects. It harbors the stratification of patients at risk of cardiotoxicity, the implementation of diagnostic tools (imaging techniques and biomarkers) for early diagnosis, preventive strategies and early treatment options for the complications. Herein, we discuss the basic knowledge for the implementation of cardio-oncology units and their role in the management of cancer patients, the diagnostic tools available to detect cardiotoxicity and the present therapeutic options.

Inequalities in the Access to Advanced Therapy in Heart Failure.

At present, heart failure (HF) is a worldwide problem, characterized by a high morbidity and mortality. In industrialized countries or regions, such as the United States, Canada, and western European countries, HF has a prevalence of 1.5% to 2.7%. Chile represents a growing economy in Latin America; however, the relatively high cost of more advanced therapies, in addition to other variables (ie, adequate and timely evaluation by HF specialists), makes access difficult for patients with HF. In this article, the authors review the principal difficulties in accessing advanced HF therapies in Chile, as a model of developing country.

Systemic oxidative stress and endothelial dysfunction is associated with an attenuated acute vascular response to inhaled prostanoid in pulmonary artery hypertension patients.

BACKGROUND: Systemic endothelial dysfunction and increased oxidative stress have been observed in pulmonary arterial hypertension (PAH). We evaluate whether oxidative stress and endothelial dysfunction are associated with acute pulmonary vascular bed response to an inhaled prostanoid in PAH patients. METHODS: Fourteen idiopathic PAH patients and 14 controls were included. Oxidative stress was assessed through plasma malondialdehyde (MDA) levels and xanthine oxidase (XO) and endothelial-bound superoxide dismutase (eSOD) activity. Brachial artery endothelial-dependent flow-mediated vasodilation (FMD) was used to evaluate endothelial function. Hemodynamic response to inhaled iloprost was assessed with transthoracic echocardiography. RESULTS: PAH patients showed impaired FMD (2.8 ± 0.6 vs. 10.7 ± 0.6%, P < .01), increased MDA levels and XO activity (0.6 ± 0.2 vs. 0.3 ± 0.2 µM, P < .01 and 0.04 ± 0.01 vs. 0.03 ± 0.01 U/mL, P = .02, respectively) and decreased eSOD activity (235 ± 23 vs. 461 ± 33 AUC, P < .01). Iloprost improved right cardiac output (3.7 ± 0.6 to 4.1 ± 1.2 L/min, P = .02) and decreased pulmonary vascular resistance (4.1 ± 1.1 to 2.9 ± 0.9 Wood U, P = .01). Changes in right cardiac output after prostanoid inhalation correlated significantly with baseline eSOD activity and FMD (Rho: 0.61, P < .01 and Rho: 0.63, P = .01, respectively). CONCLUSION: PAH patients show increased systemic oxidative stress and endothelial dysfunction markers. Response to inhaled prostanoid is inversely related to both parameters.

[Changes long term prognosis of 17 patients with pulmonary artery hypertension]. / Cambios en el pronóstico a largo plazo de la hipertensión arterial pulmonar.

BACKGROUND: Pulmonary artery hypertension (PAH) is a progressive disease with high mortality. Major advances had been made in the treatment of this condition during the last decade. AIM: To characterize the clinical evolution and mortality of a cohort of Chilean patients. MATERIAL AND METHODS: Seventeen patients with PAH diagnosed in the last 10 years in two Chilean hospitals were enrolled. Measurements at diagnosis included hemodynamic variables and 6-minute walk test. The patients were followed clinically for 3 years and the observed mortality was compared with that predicted by the prognostic equation proposed by the historic registry of the National Institutes of Health (NIH). RESULTS: The mean age of patients was 45 years and 80% had an idiopathic PAH. The mean median pulmonary artery pressure was 57 ± 15 mmHg, the cardiac index was 2.4 ± 0.7 l/min/m² and the right atrial pressure was 12 ± 8 mmHg. The 6-minute walk distance was 348 ± 98 m. All patients received anticoagulants. Eighty two percent received ambrisentan, 12% received bosentan, 29% received iloprost and 24% sildenafil. At the end of follow-up only 3 patients had died, with an observed survival rate of 88, 82 and 82% at 1, 2 and 3 years, respectively. In contrast, the survival calculated according to the predictive formula of the NIH was 67, 56 and 45%, respectively. Among surviving patients, an improvement in exercise capacity was observed after one year (p < 0.05). CONCLUSIONS: The observed survival rate was significantly better than that estimated according to historical data. Furthermore, therapy was associated with an improvement in functional capacity after one year. This prognostic improvement is consistent with data of other contemporary registries published after the NIH Registry.

[The role of uric acid in heart failure]. / Ácido úrico: una molécula con acciones paradójicas en la insuficiencia cardiaca.

Complications and mortality of heart failure are high, despite the availability of several forms of treatment. Uric acid, the end product of purine metabolism would actively participate in the pathophysiology of heart failure. However, there is no consensus about its action in cardiovascular disease. Serum uric acid would have a protective antioxidant activity. This action could help to reduce or counteract the processes that cause or appear as a result of heart failure. However, these protective properties would vanish in the intracellular environment or in highly hydrophobic areas such as atherosclerotic plaques and adipose tissue. This review discusses the paradoxical action of uric acid in the pathophysiology of heart failure.

[Myocardial lipids and creatine measured by magnetic resonance spectroscopy among patients with heart failure]. / Determinaciones de niveles de creatina y lípidos mediante espectroscopia por resonancia magnética en miocardio de pacientes con insuficiencia cardiaca no isquémica.

BACKGROUND: Heart failure (HF) is characterized, among other features, by the development of alterations in myocardial energy metabolism, involving a decrease in glucose utilization and increased free fatty acid uptake by cardiomyocytes, associated with decreased deposits of high-energy phosphates (creatine phosphate/creatine transporter). Magnetic resonance (MR) imaging allows a direct and noninvasive assessment of myocardial metabolites. AIM: To measure myocardial creatine and lipids by MR spectroscopy among patients with HF. MATERIAL AND METHODS: Cardiac MR spectroscopy (1.5 Tesla) with Hydrogen antenna and single voxel acquisition was performed in five patients with non-ischemic heart failure, aged 58 ± 9.7 years, (60% males) and 5 healthy volunteers matched for age and sex. We analyzed the signals of creatine (Cr), lipids (L) and water (W) in the interventricular septum, establishing the water/lipid (W/L) and water/creatine (W/Cr) index to normalize the values obtained. RESULTS: Among patients, left ventricular ejection fraction was 32 ± 6.9%, 60% were in functional capacity II, 60% had hypertension and one was diabetic. Spectroscopic curves showed a depletion of total Cr, evidenced by the W/ Cr index, among patients with heart failure, when compared with healthy controls (1.46 ± 1.21 and 5.96 ± 2.25 respectively, p < 0,05). Differences in myocardial lipid content, measured as the W/L index, were not significant (5.06 ± 2.66 and 1.80 ± 1.62 respectively, p = 0.08). CONCLUSIONS: Among patients with heart failure of non-ischemic etiology, there is a depletion of creatine levels measured by MR spectroscopy.

Ethnic disparities in cardiac transplantation: opportunities to improve long-term outcomes in all cardiac transplant recipients.

Ethnic disparities in cardiovascular outcomes have been increasingly recognized in the medical literature. In a recent paper in this journal, Peled et al. provide evidence that Arab Israelis may have worse outcome after cardiac transplant than their Jewish counterparts. This commentary explores possible explanations for the differing outcomes and suggests potential solutions that may improve outcomes for cardiac transplant recipients regardless of ethnicity.

Serum uric acid correlates with extracellular superoxide dismutase activity in patients with chronic heart failure.

Increased serum uric acid has been identified as an independent risk factor for cardiovascular disease. However, because of its antioxidant capacity, uric acid may play a beneficial role in endothelial function. This paradoxical relationship between uric acid and endothelial function in chronic heart failure patients remains poorly understood. Thirty-eight chronic heart failure patients (New York Heart Association functional class II-III, mean age 58+/-10 years and mean left ventricular ejection fraction 25+/-8%) and twelve age-and-sex-matched healthy controls were studied. Chronic heart failure patients showed higher uric acid levels (7.3+/-2.3 mg/dL vs. 6.1+/-0.2 mg/dL, p<0.05) and lower extracellular superoxide dismutase activity (136+/-36 U ml(-1) min(-1) vs. 203+/-61 U ml(-1) min(-1), p<0.01) and endothelium-dependent vasodilatation (4.0+/-1.6% v. 9.1+/-3.0%, p<0.01) when compared with control subjects. In chronic heart failure patients, correlations between both uric acid levels and extracellular superoxide dismutase activity (r=0.45; p<0.01), and uric acid and endothelium-dependent vasodilatation (r=0.35; p=0.03) were detected. These correlations were not observed in healthy individuals, suggesting a positive effect of uric acid on endothelial function partially mediated by modulation of extracellular superoxide dismutase activity in chronic heart failure.

Optimal length of triple therapy for H pylori eradication in a population with high prevalence of infection in Chile.

AIM: To compare the efficacy of 7-d versus 14-d triple therapy for the treatment of H pylori infection in Chile, with a prevalence of 73% in general population. METHODS: H pylori-infected patients diagnosed by rapid urease test, with non-ulcer dyspepsia or peptic ulcer disease were randomized to receive omeprazole 20 mg bid, amoxicillin 1 g bid, and clarithromycin 500 mg bid for 7 (OAC7) or 14 (OAC14) d. Primary outcome was eradication rate 6 wk after the treatment. Subgroup analysis was carried out considering the eradication rate among patients with or without peptic ulcer disease and eradication rate among smokers or non-smokers. RESULTS: One hundred and thirty-one patients were randomized to OAC7 (n = 69) or OAC14 (n = 62). The overall eradication rate (intention-to-treat) was 78.3% in OAC7 and 85.5% in OAC14 groups, without a significant difference (P =0.37). No significant difference in the eradication rate was found among the patients with peptic ulcer disease (n = 31) between the OAC7 group (85.7%) and OAC14 group (87.5%). However, smokers had an obviously lower eradication rate compared to non-smokers, particularly in the OAC7 group (57.1% in smokers vs 83.6% in non-smokers; P = 0.06). Adverse effects rate were similar between both groups. CONCLUSION: Short-term efficacy of triple therapy with OAC for 7 d is comparable to 14 d in this high-prevalence population. Longer follow-up, and studies focused to some subgroups of patients (smokers and non-ulcer patients) are necessary to support widespread use of 7-d instead of 10-14-d triple therapy in a developing country like Chile.

Cuantificación de la extrasistolía supraventricular y ventricular en el holter de 24 horas: significación pronóstica en estudios actuales / Quantification and clinical significance of supraventricular and ventricular extrasystoles in holter recordings: a review

En la actualidad existen diferencias en la interpretación y cuantificación de los extrasístoles supraventriculares y ventriculares en el Holter de ritmo cardíaco y no existe siempre una misma definición e interpretación de lo que se denomina como "escaso", "ocasional", "frecuente" o "muy frecuente". El objetivo del presente trabajo ha sido revisar las evidencias actuales y sus fundamentos en relación a la cuantificación o carga de la extrasistolía supraventricular y ventricular en un Holter de ritmo cardíaco, lo que debiera contribuir a una mayor precisión y mejor interpretación de la información cuantitativa en la práctica clínica diaria con este examen. Se revisa en la literatura el concepto de carga de extrasístoles supraventriculares y ventriculares y su relación con eventos clínicos: fibrilación auricular y accidente cerebrovascular en el caso de la extrasistolía supraventricular y mortalidad post infarto y deterioro de la función ventricular en el caso de la extrasistolía ventricular. De esta manera se cuantifica en base a la evidencia la extrasistolía supraventricular y ventricular.

Considerable differences exist in the quantification and clinical significance of both supraventricular and ventricular extrasystoles found in Holter recordings. Usually extrasystoles were classified as rare, occasional, frequent and very frequent. Current publications were analyzed regarding the frequency and clinical significance or these arrhythmias, especially in in relation to prior myocardial infarction, ventricular dysfunction, atrial fibrillation and cerebro vascular events. Tables showing limits to define the severity of supraventricular and ventricular extrasystoles are included.

Cardiomiopatía amiloídea por transtiretina: diagnóstico y manejo en la actualidad / Transthyretin amyloid cardiomyopathy: a review

RESUMEN: La cardiomiopatía amiloide por transtiretina (CATTR) es una enfermedad caracterizada por depósito extracelular de fibrillas amiloides en el miocardio, a partir de transtiretina mal plegada, generando una miocardiopatía restrictiva. Esta proteína mal plegada puede tener origen hereditario o adquirido, siendo más frecuente en adultos mayores. La CA-TTR ha surgido como una causa subdiagnosticada de insuficiencia cardíaca con fracción de eyección preservada (IC FEp). El pilar fundamental para su diagnóstico es la alta sospecha clínica, basada en diversas banderas de alerta ya que la sintomatología que provoca suele ser inespecífica. Como veremos en esta revisión, el diagnóstico puede sustentarse con la cintigrafía ósea, reservando para situaciones particulares la toma de biopsia. Con el advenimiento de nuevas terapias que impactan en la sobrevida de esta enfermedad, el tiempo para realizar el diagnóstico certero y la diferenciación de otras causas de amiloidosis cardíaca como la de cadenas livianas, se ha tornado crucial.

ABSTRACT: Transthyretin amyloid cardiomyopathy (AT-TR-CM) is a disease characterized by extracellular deposition of amyloid fibrils in the myocardium, from misfolded transthyretin, generating a restrictive cardiomyopathy. This misfolded protein may be inherited or acquired, and is more prevalent in elderly patients. ATTR-CM has emerged as an underdiagnosed cause of heart failure with preserved ejection fraction (HF-PEF). The fundamental pillarfor its diagnosis is high clinical suspicion since the symptoms are usually nonspecific. The diagnosis can be made from bone scintigraphy, reserving myocardial biopsy for particular situations. With the advent of new therapies that affect the survival of these patients, a timely diagnosis has become crucial.

Effects of carvedilol upon intra- and interventricular synchrony in patients with chronic heart failure.

Radionuclide isotopic ventriculography with phase analysis was performed in 30 patients with stable heart failure (HF), determining left ventricular (LV) and interventricular contraction synchrony at baseline and after 6 months of treatment with maximal tolerated doses of carvedilol. Patients with HF had significant ventricular dyssynchrony compared with a normal population. The 50th percentile of patients with the greatest dyssynchrony at baseline showed significant improvement in ventricular synchrony after receiving carvedilol, and this was correlated positively with a reduction in end-diastolic LV volumes.

Effects of carvedilol on oxidative stress and chronotropic response to exercise in patients with chronic heart failure.

BACKGROUND: Our previous studies suggest that the increase in heart rate from rest to peak exercise is reduced in patients with chronic heart failure (CHF) and this is associated with increased oxidative stress, as determined by malondialdehyde (MDA) plasma levels. AIM: To investigate the effects of carvedilol on the heart rate response to exercise and oxidative stress in patients with CHF. METHODS AND RESULTS: Thirty stable NYHA classes II-III CHF patients received carvedilol therapy for 6 months, at a mean maintenance dose of 25 mg (range 6.25-50 mg/day). After treatment, the patients showed a significant improvement in their functional NYHA class (p=0.013), increased left ventricular ejection fraction (LVEF) (24+/-1.4% to 31+/-2.3%, p=0.003) and 6-min walk distance (499+/-18 to 534+/-18 m, p=0.03), without changes in the peak VO2. At baseline, norepinephrine (NE) plasma levels increased with exercise (510+/-51 to 2513+/-230 pg/mL, p<0.001), and these levels were not affected by carvedilol. Chronotropic responsiveness index (increase in heart rate divided by the increase in NE from rest to peak exercise) was not changed by carvedilol (0.049+/-0.001 to 0.042+/-0.001, p=0.6). MDA levels of CHF patients decreased after treatment with carvedilol (2.4+/-0.2 to 1.1+/-0.2 microM, p<0.001), without changes in antioxidant enzyme activities. CONCLUSIONS: Carvedilol treatment in patients with CHF results in reduced oxidative stress without restoration of the chronotropic responsiveness index.

[Effects of carvedilol on functional capacity, left ventricular function, catecholamines and oxidative stress in patients with chronic heart failure]. / Efectos del carvedilol en la capacidad funcional, función ventricular izquierda, catecolaminas y estrés oxidativo en pacientes con insuficiencia cardíaca crónica.

INTRODUCTION AND OBJECTIVE: Carvedilol is an antioxidant and adrenergic antagonist with demonstrated benefits in terms of mortality from heart failure (HF). The aim of the present study was to evaluate clinical parameters, left ventricular function, oxidative stress levels and neurohumoral status at baseline and after 6 months of treatment with carvedilol in patients with chronic HF. PATIENTS AND METHOD: Thirty patients with chronic HF that was stable without beta blocker treatment were included. Functional class was II or III, and left ventricular ejection fraction (LVEF) was < 40%. Mahler score, distance walked in 6 min, peak oxygen consumption, LVEF, plasma catecholamine (norepinephrine) concentration and oxidative stress parameters were evaluated at baseline and after 6 months of treatment with carvedilol. RESULTS: Mean age was 59 (2) years, and 23 patients were men. After 6 months of treatment there were clinical improvements as measured by the Mahler score (from 6.8 to 11.0 points; P=.001) and the 6-min walk distance (from 499 [18] to 534 [17] m; P =.032), but no changes in peak oxygen consumption. The LVEF increased from 24 (1) to 31 (2)% (P=.003). In patients with chronic HF, plasma malondialdehyde concentration was significantly lower after 6 months (decrease from 2.4 [0.2] to 1.1 [0.2] micromol/l; P<.001). No significant changes were observed in plasma catecholamine levels or antioxidant enzyme activities. CONCLUSIONS: In patients with chronic HF, carvedilol treatment for 6 months was associated with clinical improvements, increased left ventricular function and decreased plasma concentrations of malondialdehyde, with no changes in plasma catecholamine levels.