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AIMS: Compared with those without obesity, patients with obesity-related heart failure with preserved ejection fraction (HFpEF) have worse symptoms, haemodynamics, and outcomes. Current weight loss strategies (diet, drug, and surgical) work through decreased energy intake rather than increased expenditure and cause significant loss of skeletal muscle mass in addition to adipose tissue. This may have adverse implications for patients with HFpEF, who already have reduced skeletal muscle mass and function and high rates of physical frailty. Mitochondrial uncoupling agents may have unique beneficial effects by producing weight loss via increased catabolism rather than reduced caloric intake, thereby causing loss of adipose tissue while sparing skeletal muscle. HU6 is a controlled metabolic accelerator that is metabolized to the mitochondrial uncoupling agent 2,4-dinotrophenol. HU6 selectively increases carbon oxidation from fat and glucose while also decreasing toxic reactive oxygen species (ROS) production. In addition to sparing skeletal muscle loss, HU6 may have other benefits relevant to obesity-related HFpEF, including reduced specific tissue depots contributing to HFpEF; improved glucose utilization; and reduction in systemic inflammation via both decreased ROS production from mitochondria and decreased cytokine elaboration from excess, dysfunctional adipose. METHODS: We describe the rationale and design of HuMAIN-HFpEF, a Phase 2a randomized, double-blind, placebo-controlled, dose-titration, parallel-group trial in patients with obesity-related HFpEF to evaluate the effects of HU6 on weight loss, body composition, exercise capacity, cardiac structure and function, metabolism, and inflammation, and identify optimal dosage for future Phase 3 trials. CONCLUSIONS: HuMAIN will test a promising novel agent for obesity-related HFpEF.
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Importance: Although the results of A Study to Evaluate the Corvia Medical Inc IASD System II to Reduce Elevated Left Atrial Pressure in Patients with Heart Failure (REDUCE LAP-HF II) trial were neutral overall, atrial shunt therapy demonstrated potential efficacy in responders (no latent pulmonary vascular disease and no cardiac rhythm management device). Post hoc analyses were conducted to evaluate the effect of shunt vs sham stratified by responder status. Objective: To evaluate the effect of atrial shunt vs sham control on cardiac structure/function in the overall study and stratified by responder status. Design, Setting, and Participants: This was a sham-controlled randomized clinical trial of an atrial shunt device in heart failure with preserved ejection fraction (HFpEF)/HF with mildly reduced EF (HFmrEF). Trial participants with evaluable echocardiography scans were recruited from 89 international medical centers. Data were analyzed from April 2023 to January 2024. Interventions: Atrial shunt device or sham control. Main Outcome Measures: Changes in echocardiographic measures from baseline to 1, 6, 12, and 24 months after index procedure. Results: The modified intention-to-treat analysis of the REDUCE LAP-HF II trial included 621 randomized patients (median [IQR] age, 72.0 [66.0-77.0] years; 382 female [61.5%]; shunt arm, 309 [49.8%]; sham control arm, 312 [50.2%]). Through 24 months, 212 of 217 patients (98%) in the shunt arm with evaluable echocardiograms had patent shunts. In the overall trial population, the shunt reduced left ventricular (LV) end-diastolic volume (mean difference, -5.65 mL; P <.001), left atrial (LA) minimal volume (mean difference, -2.8 mL; P =.01), and improved LV systolic tissue Doppler velocity (mean difference, 0.69 cm/s; P <.001) and LA emptying fraction (mean difference, 1.88 percentage units; P =.02) compared with sham. Shunt treatment also increased right ventricular (RV; mean difference, 9.58 mL; P <.001) and right atrial (RA; mean difference, 9.71 mL; P <.001) volumes but had no effect on RV systolic function, pulmonary artery pressure, or RA pressure compared with sham. In the shunt arm, responders had smaller increases in RV end-diastolic volume (mean difference, 5.71 mL vs 15.18 mL; interaction P =.01), RV end-systolic volume (mean difference, 1.58 mL vs 7.89 mL; interaction P =.002), and RV/LV ratio (mean difference, 0.07 vs 0.20; interaction P <.001) and larger increases in transmitral A wave velocity (mean difference, 5.08 cm/s vs -1.97 cm/s; interaction P =.02) compared with nonresponders randomized to the shunt, suggesting greater ability to accommodate shunted blood through the pulmonary circulation enabling LA unloading. Conclusions and Relevance: In this post hoc analysis of the REDUCE LAP-HF II trial, over 2 years of follow-up, atrial shunting led to reverse remodeling of left-sided chambers and increases in volume of right-sided chambers consistent with the shunt flow but no change in RV systolic function compared with sham. Changes in cardiac structure/function were more favorable in responders compared with nonresponders treated with the shunt, supporting the previously identified responder group hypothesis and mechanism, although further evaluation with longer follow-up is needed. Trial Registration: ClinicalTrials.gov Identifier: NCT03088033.
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Insuficiencia Cardíaca , Volumen Sistólico , Humanos , Femenino , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/terapia , Masculino , Volumen Sistólico/fisiología , Anciano , Persona de Mediana Edad , Ecocardiografía , Atrios Cardíacos/fisiopatología , Atrios Cardíacos/diagnóstico por imagen , Resultado del TratamientoRESUMEN
Epigenetic mechanisms are increasingly understood to have major impacts across ecology. However, one molecular epigenetic mechanism, DNA methylation, currently dominates the literature. A second mechanism, histone modification, is likely important to ecologically relevant phenotypes and thus warrants investigation, especially because molecular interplay between methylation and histone acetylation can strongly affect gene expression. There are a limited number of histone acetylation studies on non-model organisms, yet those that exist show that it can impact gene expression and phenotypic plasticity. Wild birds provide an excellent system to investigate histone acetylation, as free-living individuals must rapidly adjust to environmental change. Here, we screen histone acetylation in the house sparrow (Passer domesticus); we studied this species because DNA methylation was important in the spread of this bird globally. This species has one of the broadest geographic distributions in the world, and part of this success is related to the way that it uses methylation to regulate its gene expression. Here, we verify that a commercially available assay that was developed for mammals can be used in house sparrows. We detected high variance in histone acetylation among individuals in both liver and spleen tissue. Further, house sparrows with higher epigenetic potential in the Toll Like Receptor-4 (TLR-4) promoter (i.e., CpG content) had higher histone acetylation in liver. Also, there was a negative correlation between histone acetylation in spleen and TLR-4 expression. In addition to validating a method for measuring histone acetylation in wild songbirds, this study also shows that histone acetylation is related to epigenetic potential and gene expression, adding a new study option for ecological epigenetics.
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OBJECTIVE: Splanchnic vasoconstriction augments transfer of blood volume from the abdomen into the thorax, which may increase filling pressures and hemodynamic congestion in patients with noncompliant hearts. Therapeutic interruption of splanchnic nerve activity holds promise to reduce hemodynamic congestion in patients with heart failure with preserved ejection fraction (HFpEF). Here we describe (1) the rationale and design of the first sham-controlled, randomized clinical trial of splanchnic nerve ablation for HFpEF and (2) the 12-month results of the lead-in (open-label) trial's participants. METHODS: REBALANCE-HF is a prospective, multicenter, randomized, double-blinded, sham-controlled clinical trial of endovascular, transcatheter, right-sided greater splanchnic nerve ablation for volume management (SAVM) in patients with HFpEF. The primary objectives are to evaluate the safety and efficacy of SAVM and identify responder characteristics to inform future studies. The trial consists of an open-label lead-in phase followed by the randomized, sham-controlled phase. The primary efficacy endpoint is the reduction in pulmonary capillary wedge pressure (PCWP) at 1-month follow-up compared to baseline during passive leg raise and 20W exercise. Secondary and exploratory endpoints include health status (Kansas City Cardiomyopathy Questionnaire), 6-minute walk test distance, New York Heart Association class, and NTproBNP levels at 3, 6 and 12 months. The primary safety endpoint is device- or procedure-related serious adverse events at the 1-month follow-up. RESULTS: The lead-in phase of the study, which enrolled 26 patients with HFpEF who underwent SAVM, demonstrated favorable safety outcomes and reduction in exercise PCWP at 1 month post-procedure and improvements in all secondary endpoints at 6 and 12 months of follow-up. The randomized phase of the trial (nâ¯=â¯44 SAVM; nâ¯=â¯46 sham) has completed enrollment, and follow-up is ongoing. CONCLUSION: REBALANCE-HF is the first sham-controlled randomized clinical trial of greater splanchnic nerve ablation in HFpEF. Initial 12-month open-label results are promising, and the results of the randomized portion of the trial will inform the design of a future pivotal clinical trial. SAVM may offer a promising therapeutic option for patients with HFpEF. TRIAL REGISTRATION: NCT04592445.
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Insuficiencia Cardíaca , Nervios Esplácnicos , Volumen Sistólico , Humanos , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/cirugía , Insuficiencia Cardíaca/terapia , Volumen Sistólico/fisiología , Método Doble Ciego , Nervios Esplácnicos/cirugía , Masculino , Femenino , Estudios Prospectivos , Procedimientos Endovasculares/métodos , Resultado del Tratamiento , Anciano , Persona de Mediana Edad , Técnicas de Ablación/métodos , Estudios de SeguimientoRESUMEN
AIMS: Obesity is causally related to the development of heart failure with preserved ejection fraction (HFpEF) but complicates the diagnosis and treatment of this disorder. We aimed to determine the relationship between severity of obesity and clinical, echocardiographic and haemodynamic parameters in a large cohort of patients with documented HFpEF. METHODS AND RESULTS: The REDUCE LAP-HF II trial randomized 626 patients with ejection fraction ≥40% and exercise pulmonary capillary wedge pressure (PCWP) ≥25 mmHg to atrial shunt or sham procedure. We tested for associations between body mass index (BMI), clinical characteristics, cardiac structural and functional abnormalities, physical limitations, quality of life and outcomes with atrial shunt therapy. Overall, 60.9% of patients had BMI ≥30 kg/m2 . As the severity of obesity increased, symptoms (Kansas City Cardiomyopathy Questionnaire score) and 6-min walk distance worsened. More severe obesity was associated with lower natriuretic peptide levels despite more cardiac remodelling, higher cardiac filling pressures, and higher cardiac output. Lower cut points for E/e' were needed to identify elevated PCWP in more obese patients. Strain measurements in all four chambers were maintained as BMI increased. Pulmonary vascular resistance at rest and exercise decreased with higher BMI. Obesity was associated with more first and recurrent heart failure events. However, there was no significant interaction between obesity and treatment effects of the atrial shunt. CONCLUSIONS: Increasing severity of obesity was associated with greater cardiac remodelling, higher right and left ventricular filling pressures, higher cardiac output and increased subsequent heart failure events. Despite significant obesity, many HFpEF patients have preserved right heart and pulmonary vascular function and thus, may be appropriate candidates for atrial shunt therapy.
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Flavinas , Insuficiencia Cardíaca , Luciferasas , Humanos , Volumen Sistólico , Cateterismo Cardíaco , Remodelación Ventricular , Calidad de Vida , Atrios Cardíacos , Obesidad/complicaciones , Función Ventricular IzquierdaRESUMEN
BACKGROUND: Morbidity and mortality for acute pulmonary embolism (PE) remain high. Therapies such as catheter-directed thrombolysis may improve outcomes, but these are generally reserved for higher-risk patients. Imaging may help guide the use of the newer therapies, but current guidelines focus more on clinical factors. Our goal was to create a risk model that incorporated quantitative echocardiographic and computed tomography (CT) measures of right ventricular (RV) size and function, thrombus burden, and serum biomarkers of cardiac overload or injury. METHODS: This was a retrospective study of 150 patients evaluated by a PE response team. Echocardiography was performed within 48 hours of diagnosis. Computed tomography measures included RV/left ventricular (LV) ratio and thrombus load (Qanadli score). Echocardiography was used to obtain various quantitative measures of RV function. We compared characteristics of those who met the primary endpoint (7-day mortality and clinical deterioration) to those who did not. Receiver operating curve analysis was used to assess the performance of different combinations of clinically relevant features and the association with adverse outcomes. RESULTS: Fifty-two percent of patients were female, with age 62 ± 17 years, systolic blood pressure 123 ± 25 mm Hg, heart rate 98 ± 19, troponin 3.2 ± 35 ng/dL, and b-type natriuretic peptide (BNP) 467 ± 653. Fourteen (9.3%) were treated with systemic thrombolytics, 27 (18%) underwent catheter-directed thrombolytics, 23 (15%) were intubated or required vasopressors, and 14 (9.3%) died. Patients who met the primary endpoint (44%) versus those who did not (56%) had lower RV S' (6.6 vs 11.9 cm/sec; P < .001) and RV free wall strain (-10.9% vs -13.6%; P = .005), higher RV/LV ratio on CT, and higher serum BNP and troponin levels. Receiver operating curve analysis demonstrated an area under the curve of 0.89 for a model that included RV S', RV free wall strain and tricuspid annular plane systolic excursion/RV systolic pressure ratio from echo, thrombus load and RV/LV ratio from CT, and troponin and BNP levels. CONCLUSION: A combination of clinical, echo, and CT findings that reflect the hemodynamic effects of the embolism identified patients with adverse events related to acute PE. Optimized scoring systems that focus on reversible abnormalities attributable to PE may allow more appropriate triaging of intermediate- to high-risk patients with PE for early interventional strategy.
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Embolia Pulmonar , Disfunción Ventricular Derecha , Humanos , Femenino , Persona de Mediana Edad , Anciano , Masculino , Estudios Retrospectivos , Embolia Pulmonar/diagnóstico por imagen , Embolia Pulmonar/complicaciones , Ecocardiografía , Tomografía Computarizada por Rayos X , Troponina , Enfermedad Aguda , Disfunción Ventricular Derecha/diagnóstico por imagenRESUMEN
BACKGROUND: Many patients with heart failure and preserved ejection fraction have no overt volume overload and normal resting left atrial (LA) pressure. OBJECTIVES: This study sought to characterize patients with normal resting LA pressure (pulmonary capillary wedge pressure [PCWP] <15 mm Hg) but exercise-induced left atrial hypertension (EILAH). METHODS: The REDUCE LAP-HF II (A Study to Evaluate the Corvia Medical, Inc. IASD System II to Reduce Elevated Left Atrial Pressure in Patients With Heart Failure) trial randomized 626 patients with ejection fraction ≥40% and exercise PCWP ≥25 mm Hg to atrial shunt or sham procedure. The primary trial outcome, a hierarchical composite of death, heart failure hospitalization, intensification of diuretics, and change in health status was compared between patients with EILAH and those with heart failure and resting left atrial hypertension (RELAH). RESULTS: Patients with EILAH (29%) had similar symptom severity, but lower natriuretic peptide levels, higher 6-minute walk distance, less atrial fibrillation, lower left ventricular mass, smaller LA volumes, lower E/e', and better LA strain. PCWP was lower at rest, but had a larger increase with exercise in EILAH. Neither group as a whole had a significant effect from shunt therapy vs sham. Patients with EILAH were more likely to have characteristics associated with atrial shunt responsiveness (peak exercise pulmonary vascular resistance <1.74 WU) and no pacemaker (63% vs 46%; P < 0.001). The win ratio for the primary outcome was 1.56 (P = 0.08) in patients with EILAH and 1.51 (P = 0.04) in those with RELAH when responder characteristics were present. CONCLUSIONS: Patients with EILAH had similar symptom severity but less advanced myocardial and pulmonary vascular disease. This important subgroup may be difficult to diagnose without invasive exercise hemodynamics, but it has characteristics associated with favorable response to atrial shunt therapy. (A Study to Evaluate the Corvia Medical, Inc. IASD System II to Reduce Elevated Left Atrial Pressure in Patients With Heart Failure [REDUCE LAP-HF TRIAL II]; NCT03088033).
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Fibrilación Atrial , Insuficiencia Cardíaca , Hipertensión , Humanos , Fibrilación Atrial/complicaciones , Fibrilación Atrial/terapia , Cateterismo Cardíaco , Insuficiencia Cardíaca/complicaciones , Insuficiencia Cardíaca/terapia , Insuficiencia Cardíaca/diagnóstico , Volumen Sistólico/fisiología , Función Ventricular IzquierdaRESUMEN
AIMS: Elevated left atrial (LA) pressure is a pathophysiologic hallmark of heart failure with preserved ejection fraction (HFpEF). Chronically elevated LA pressure leads to LA enlargement, which may impair LA function and increase pulmonary pressures. We sought to evaluate the relationship between LA volume and pulmonary arterial haemodynamics in patients with HFpEF. METHODS AND RESULTS: Data from 85 patients (aged 69 ± 8 years) who underwent exercise right heart catheterization and echocardiography were retrospectively analysed. All had symptoms of heart failure, left ventricular ejection fraction ≥50% and haemodynamic features of HFpEF. Patients were divided into LA volume index-based tertiles (≤34 ml/m2 , >34 to ≤45 ml/m2 , >45 ml/m2 ). A subgroup analysis was performed in patients with recorded LA global reservoir strain (n = 60), with reduced strain defined as ≤24%. Age, sex, body surface area and left ventricular ejection fraction were similar between volume groups. LA volume was associated with blunted increases in cardiac output with exercise (padjusted <0.001), higher resting mean pulmonary artery pressure (padjusted = 0.003), with similar wedge pressure (padjusted = 1). Pulmonary vascular resistance (PVR) increased with increasing LA volume (padjusted <0.001). Larger LA volumes featured reduced LA strain (padjusted <0.001), with reduced strain associated with reduced PVR-compliance time (0.34 [0.28-0.40] vs. 0.38 [0.33-0.43], p = 0.03). CONCLUSION: Increasing LA volume may be associated with more advanced pulmonary vascular disease in HFpEF, featuring higher PVR and pulmonary pressures. Reduced LA function, worse at increasing LA volumes, is associated with a disrupted PVR-compliance relationship, further augmenting impaired pulmonary haemodynamics.
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Fibrilación Atrial , Insuficiencia Cardíaca , Enfermedades Vasculares , Humanos , Volumen Sistólico/fisiología , Función Ventricular Izquierda , Estudios RetrospectivosRESUMEN
AIMS: Obesity is common and associated with unique phenotypic features in heart failure with preserved ejection fraction (HFpEF). Therefore, understanding the efficacy and safety of new therapies in HFpEF patients with obesity is important. The effects of dapagliflozin were examined according to body mass index (BMI) among patients in the Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure trial. METHODS AND RESULTS: Body mass index was analysed by World Health Organization (WHO) categories and as a continuous variable using restricted cubic splines. Body mass index ranged from 15.2 to 50â kg/m2 with a mean value of 29.8 (standard deviation ± 6.1) kg/m2. The proportions, by WHO category, were: normal weight 1343 (21.5%); overweight 2073 (33.1%); Class I obesity 1574 (25.2%); Class II obesity 798 (12.8%); and Class III obesity 415 (6.6%). Compared with placebo, dapagliflozin reduced the risk of the primary outcome to a similar extent across these categories: hazard ratio (95% confidence interval): 0.89 (0.69-1.15), 0.87 (0.70-1.08), 0.74 (0.58-0.93), 0.78 (0.57-1.08), and 0.72 (0.47-1.08), respectively (P-interaction = 0.82). The placebo-corrected change in Kansas City Cardiomyopathy Questionnaire total symptom score with dapagliflozin at 8 months was: 0.9 (-1.1, 2.8), 2.5 (0.8, 4.1), 1.9 (-0.1, 3.8), 2.7 (-0.5, 5.8), and 8.6 (4.0, 13.2) points, respectively (P-interaction = 0.03). The placebo-corrected change in weight at 12 months was: -0.88 (-1.28, -0.47), -0.65 (-1.04, -0.26), -1.42 (-1.89, -0.94), -1.17 (-1.94, -0.40), and -2.50 (-4.4, -0.64) kg (P-interaction = 0.002). CONCLUSIONS: Obesity is common in patients with HFpEF and is associated with higher rates of heart failure hospitalization and worse health status. Treatment with dapagliflozin improves cardiovascular outcomes across the spectrum of BMI, leads to greater symptom improvement in patients with obesity, compared with those without, and has the additional benefit of causing modest weight loss.
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Insuficiencia Cardíaca , Humanos , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/complicaciones , Índice de Masa Corporal , Volumen Sistólico , Obesidad/complicacionesRESUMEN
AIMS: In heart failure (HF) with preserved ejection fraction (HFpEF), excessive redistribution of blood volume into the central circulation leads to elevations of intracardiac pressures with exercise limitations. Splanchnic ablation for volume management (SAVM) has been proposed as a therapeutic intervention. Here we present preliminary safety and efficacy data from the initial roll-in cohort of the REBALANCE-HF trial. METHODS AND RESULTS: The open-label (roll-in) arm of REBALANCE-HF will enrol up to 30 patients, followed by the randomized, sham-controlled portion of the trial (up to 80 additional patients). Patients with HF, left ventricular ejection fraction (LVEF) ≥50%, and invasive peak exercise pulmonary capillary wedge pressure (PCWP) ≥25 mmHg underwent SAVM. Baseline and follow-up assessments included resting and exercise PCWP, New York Heart Association (NYHA) class, Kansas City Cardiomyopathy Questionnaire (KCCQ), 6-min walk test, and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Efficacy and safety were assessed at 1 and 3 months. Here we report on the first 18 patients with HFpEF that have been enrolled into the roll-in, open-label arm of the study across nine centres; 14 (78%) female; 16 (89%) in NYHA class III; and median (interquartile range) age 75.2 (68.4-81) years, LVEF 61.0 (56.0-63.2)%, and average (standard deviation) 20 W exercise PCWP 36.4 (±8.6) mmHg. All 18 patients were successfully treated. Three non-serious moderate device/procedure-related adverse events were reported. At 1-month, the mean PCWP at 20 W exercise decreased from 36.4 (±8.6) to 28.9 (±7.8) mmHg (p < 0.01), NYHA class improved by at least one class in 33% of patients (p = 0.02) and KCCQ score improved by 22.1 points (95% confidence interval 9.4-34.2) (p < 0.01). CONCLUSION: The preliminary open-label results from the multicentre REBALANCE-HF roll-in cohort support the safety and efficacy of SAVM in HFpEF. The findings require confirmation in the ongoing randomized, sham-controlled portion of the trial.
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Insuficiencia Cardíaca , Anciano , Femenino , Insuficiencia Cardíaca/cirugía , Humanos , Masculino , Presión Esfenoidal Pulmonar , Nervios Esplácnicos , Volumen Sistólico , Función Ventricular IzquierdaRESUMEN
Metabolic risk for cardiovascular and other systems includes much more than just LDL cholesterol. This JCL Roundtable brings together 3 experts to address new opportunities to reduce the risks posed by obesity, diabetes, and fatty liver disease. Successful nutritional approaches to weight loss are diverse and need to be matched with individual preferences. Topiramate plus extended-release phentermine has been shown to promote meaningful weight loss in randomized trials, but the patented drug combination is expensive. Clinical experience suggests that generic topiramate and phentermine may also be effective. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) have shown favorable tolerability and efficacy for cardiovascular disease in randomized trials, an achievement without precedent among earlier diabetes medications. These 2 drug classes differ in their effects. GLP-1 RAs decrease atherosclerotic cardiovascular events and also decrease hemoglobin A1c, body weight, blood pressure, and possibly diabetic renal disease. SGLT2 inhibitors are effective in reducing heart failure events even among nondiabetic patients. They also decrease progression of diabetic renal disease. The presence of nonalcoholic fatty liver disease signifies risk for atherosclerotic cardiovascular disease as well as cirrhosis and serious hepatic decompensation, including hepatocellular carcinoma. The key to identifying cirrhosis risk is to assess pre-emptively liver fibrosis, which can be predicted initially with blood test risk scores (e.g., FIB-4 index) and more definitively by transient elastography and other imaging techniques and/or liver biopsy. Some medications approved for the treatment of type 2 diabetes may reduce liver fat (SGLT2 inhibitors, insulin) or even reverse steatohepatitis in paired liver biopsy studies (GLP-1 RAs or pioglitazone) Overall the field of preventive metabolic medicine is expanding. Clinical lipidologists should become familiar with recent advances.
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Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 2 , Nefropatías Diabéticas , Enfermedad del Hígado Graso no Alcohólico , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Enfermedades Cardiovasculares/complicaciones , Enfermedades Cardiovasculares/tratamiento farmacológico , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Femenino , Péptido 1 Similar al Glucagón/uso terapéutico , Receptor del Péptido 1 Similar al Glucagón/agonistas , Factores de Riesgo de Enfermedad Cardiaca , Humanos , Hipoglucemiantes/uso terapéutico , Cirrosis Hepática/complicaciones , Cirrosis Hepática/tratamiento farmacológico , Masculino , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Obesidad/complicaciones , Obesidad/tratamiento farmacológico , Fentermina/uso terapéutico , Factores de Riesgo , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Topiramato/uso terapéutico , Pérdida de PesoRESUMEN
In cardiology clinic visits, the discussion of optimal dietary patterns for prevention and management of cardiovascular disease is usually very limited. Herein, we explore the benefits and risks of various dietary patterns, including intermittent fasting, low carbohydrate, Paleolithic, whole food plant-based diet, and Mediterranean dietary patterns within the context of cardiovascular disease to empower clinicians with the evidence and information they need to maximally benefit their patients.
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Enfermedades Cardiovasculares , Dieta Mediterránea , Enfermedades Cardiovasculares/prevención & control , Ayuno , HumanosRESUMEN
BACKGROUND: Placement of an interatrial shunt device reduces pulmonary capillary wedge pressure during exercise in patients with heart failure and preserved or mildly reduced ejection fraction. We aimed to investigate whether an interatrial shunt can reduce heart failure events or improve health status in these patients. METHODS: In this randomised, international, blinded, sham-controlled trial performed at 89 health-care centres, we included patients (aged ≥40 years) with symptomatic heart failure, an ejection fraction of at least 40%, and pulmonary capillary wedge pressure during exercise of at least 25 mm Hg while exceeding right atrial pressure by at least 5 mm Hg. Patients were randomly assigned (1:1) to receive either a shunt device or sham procedure. Patients and outcome assessors were masked to randomisation. The primary endpoint was a hierarchical composite of cardiovascular death or non-fatal ischemic stroke at 12 months, rate of total heart failure events up to 24 months, and change in Kansas City Cardiomyopathy Questionnaire overall summary score at 12 months. Pre-specified subgroup analyses were conducted for the heart failure event endpoint. Analysis of the primary endpoint, all other efficacy endpoints, and safety endpoints was conducted in the modified intention-to-treat population, defined as all patients randomly allocated to receive treatment, excluding those found to be ineligible after randomisation and therefore not treated. This study is registered with ClinicalTrials.gov, NCT03088033. FINDINGS: Between May 25, 2017, and July 24, 2020, 1072 participants were enrolled, of whom 626 were randomly assigned to either the atrial shunt device (n=314) or sham procedure (n=312). There were no differences between groups in the primary composite endpoint (win ratio 1·0 [95% CI 0·8-1·2]; p=0·85) or in the individual components of the primary endpoint. The prespecified subgroups demonstrating a differential effect of atrial shunt device treatment on heart failure events were pulmonary artery systolic pressure at 20W of exercise (pinteraction=0·002 [>70 mm Hg associated with worse outcomes]), right atrial volume index (pinteraction=0·012 [≥29·7 mL/m2, worse outcomes]), and sex (pinteraction=0·02 [men, worse outcomes]). There were no differences in the composite safety endpoint between the two groups (n=116 [38%] for shunt device vs n=97 [31%] for sham procedure; p=0·11). INTERPRETATION: Placement of an atrial shunt device did not reduce the total rate of heart failure events or improve health status in the overall population of patients with heart failure and ejection fraction of greater than or equal to 40%. FUNDING: Corvia Medical.
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Cateterismo Cardíaco , Insuficiencia Cardíaca , Adulto , Cateterismo Cardíaco/instrumentación , Flavinas , Atrios Cardíacos/cirugía , Insuficiencia Cardíaca/fisiopatología , Humanos , Luciferasas , Masculino , Volumen SistólicoAsunto(s)
Adiposidad , Obesidad , Tamaño Corporal , Corazón , Humanos , Obesidad/complicaciones , Obesidad/diagnósticoRESUMEN
Heart failure with preserved ejection fraction is associated with elevated left atrial pressure during exercise. Sodium-glucose cotransporter-2 inhibitors have demonstrated the evidence of benefit in heart failure with preserved ejection fraction, but even with this treatment, heart failure hospitalizations remain high, and improvements in quality of life scores are modest. Thus, there is growing interest in nonpharmacological methods of limiting the rise in left atrial pressure during exertion. Creation of an interatrial shunt (IAS) may unload the left heart during exercise. Multiple implant or nonimplant IAS procedures are under investigation. Implantation of the most studied device results in 3 to 5 mm Hg decreases in pulmonary capillary wedge pressure during exercise, no increase in incidence of stroke, stable increases in Qp/Qs (1.2-1.3), and mild right heart enlargement without change in function out to at least a year after treatment. The findings from the first large randomized controlled trial of an atrial shunt have recently been published. For the population as a whole, implantation of the atrial shunt device appeared to be safe but did not provide clinical benefit. However, prespecified and post-hoc analyses have demonstrated that men, patients with larger right atrial volumes, and those with pulmonary artery systolic pressure >70 mm Hg at 20 W exercise had worse outcomes with IAS therapy, whereas those with peak exercise pulmonary vascular resistance <1.74 Wood units and absence of a pacemaker represented a potential responder group. Here, we summarize the results of the published data and the current IAS therapies under investigation. We also highlight unanswered questions in this field of inquiry.
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Of the various medical therapies for heart failure (HF), sacubitril/valsartan is a first-in-class angiotensin receptor-neprilysin inhibitor that combines sacubitril, a pro-drug that is further metabolized to the neprilysin inhibitor sacubitrilat, and the angiotensin II type 1 receptor blocker valsartan. Inhibition of neprilysin and blockade of the angiotensin II type 1 receptor with sacubitril/valsartan increases vasoactive peptide levels, increasing vasodilation, natriuresis, and diuresis. Left ventricular ejection fraction (LVEF) is widely used to classify HF, to assist with clinical decision-making, for patient selection in HF clinical trials, and to optimize the benefits of sacubitril/valsartan in HF. However, as HF is a complex syndrome that occurs on a continuum of overlapping and changing phenotypes, patient classification based solely on LVEF becomes problematic. LVEF measurement can be imprecise, have low reproducibility, and often changes over time. LVEF may not accurately reflect inherent disease heterogeneity and complexity, and the addition of alternate criteria to LVEF may improve phenotyping of HF and help guide treatment choices. Sacubitril/valsartan may work, in part, by mechanisms that are not directly related to the LVEF. For example, this drug may exert antifibrotic and neurohumoral modulatory effects through inhibition or activation of several signaling pathways. In this review, we discuss markers of cardiac remodeling, fibrosis, systemic inflammation; activation of neurohormonal pathways, including the natriuretic system and the sympathetic nervous system; the presence of comorbidities; patient characteristics; hemodynamics; and HF signs and symptoms that may all be used to (1) better understand the mechanisms of action of sacubitril/valsartan and (2) help to identify subsets of patients who might benefit from treatment, regardless of LVEF.