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Obesity is associated with important changes in cardiac energetics and function, and an increased risk of adverse cardiovascular outcomes. Multi-nuclear MRS and MRI techniques have the potential to provide a comprehensive non-invasive assessment of cardiac metabolic perturbation in obesity. A rat model of obesity was created by high-fat diet feeding. This model was characterized using in vivo hyperpolarized [1-13C]pyruvate and [2-13C]pyruvate MRS, echocardiography and perfused heart 31P MRS. Two groups of obese rats were subsequently treated with either caloric restriction or the glucagon-like peptide-1 analogue/agonist liraglutide, prior to reassessment. The model recapitulated cardiovascular consequences of human obesity, including mild left ventricular hypertrophy, and diastolic, but not systolic, dysfunction. Hyperpolarized 13C and 31P MRS demonstrated that obesity was associated with reduced myocardial pyruvate dehydrogenase flux, altered cardiac tricarboxylic acid (TCA) cycle metabolism, and impaired myocardial energetic status (lower phosphocreatine to adenosine triphosphate ratio and impaired cardiac ΔG~ATP). Both caloric restriction and liraglutide treatment were associated with normalization of metabolic changes, alongside improvement in cardiac diastolic function. In this model of obesity, hyperpolarized 13C and 31P MRS demonstrated abnormalities in cardiac metabolism at multiple levels, including myocardial substrate selection, TCA cycle, and high-energy phosphorus metabolism. Metabolic changes were linked with impairment of diastolic function and were reversed in concert following either caloric restriction or liraglutide treatment. With hyperpolarized 13C and 31P techniques now available for human use, the findings support a role for multi-nuclear MRS in the development of new therapies for obesity.
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BACKGROUND: Type 2 diabetes (T2D) is characterized by insulin resistance (IR) and dysregulated insulin secretion. Glucagon-like peptide-1 receptor agonist liraglutide promotes insulin secretion, whereas thiazolidinedione-pioglitazone decreases IR. OBJECTIVES: This study aimed to compare the efficacies of increasing insulin secretion vs decreasing IR strategies for improving myocardial perfusion, energetics, and function in T2D via an open-label randomized crossover trial. METHODS: Forty-one patients with T2D (age 63 years [95% CI: 59-68 years], 27 [66%] male, body mass index 27.8 kg/m2) [95% CI: 26.1-29.5 kg/m2)]) without cardiovascular disease were randomized to liraglutide or pioglitazone for a 16-week treatment followed by an 8-week washout and a further 16-week treatment with the second trial drug. Participants underwent rest and dobutamine stress 31phosphorus magnetic resonance spectroscopy and cardiovascular magnetic resonance for measuring the myocardial energetics index phosphocreatine to adenosine triphosphate ratio, myocardial perfusion (rest, dobutamine stress myocardial blood flow, and myocardial perfusion reserve), left ventricular (LV) volumes, systolic and diastolic function (mitral in-flow E/A ratio), before and after treatment. The 6-minute walk-test was used for functional assessments. RESULTS: Pioglitazone treatment resulted in significant increases in LV mass (96 g [95% CI: 68-105 g] to 105 g [95% CI: 74-115 g]; P = 0.003) and mitral-inflow E/A ratio (1.04 [95% CI: 0.62-1.21] to 1.34 [95% CI: 0.70-1.54]; P = 0.008), and a significant reduction in LV concentricity index (0.79 mg/mL [95% CI: 0.61-0.85 mg/mL] to 0.73 mg/mL [95% CI: 0.56-0.79 mg/mL]; P = 0.04). Liraglutide treatment increased stress myocardial blood flow (1.62 mL/g/min [95% CI: 1.19-1.75 mL/g/min] to 2.08 mL/g/min [95% CI: 1.57-2.24 mL/g/min]; P = 0.01) and myocardial perfusion reserve (2.40 [95% CI: 1.55-2.68] to 2.90 [95% CI: 1.83-3.18]; P = 0.01). Liraglutide treatment also significantly increased the rest (1.47 [95% CI: 1.17-1.58] to 1.94 [95% CI: 1.52-2.08]; P =0.00002) and stress phosphocreatine to adenosine triphosphate ratio (1.32 [95% CI: 1.05-1.42] to 1.58 [95% CI: 1.19-1.71]; P = 0.004) and 6-minute walk distance (488 m [95% CI: 458-518 m] to 521 m [95% CI: 481-561 m]; P = 0.009). CONCLUSIONS: Liraglutide treatment resulted in improved myocardial perfusion, energetics, and 6-minute walk distance in patients with T2D, whereas pioglitazone showed no effect on these parameters (Lean-DM [Targeting Beta-cell Failure in Lean Patients With Type 2 Diabetes]; NCT04657939).
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Estudios Cruzados , Diabetes Mellitus Tipo 2 , Tolerancia al Ejercicio , Hipoglucemiantes , Liraglutida , Pioglitazona , Humanos , Masculino , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/fisiopatología , Diabetes Mellitus Tipo 2/metabolismo , Persona de Mediana Edad , Liraglutida/uso terapéutico , Liraglutida/farmacología , Femenino , Anciano , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/farmacología , Tolerancia al Ejercicio/efectos de los fármacos , Tolerancia al Ejercicio/fisiología , Pioglitazona/uso terapéutico , Circulación Coronaria/efectos de los fármacos , Circulación Coronaria/fisiología , Resistencia a la Insulina/fisiologíaRESUMEN
In health, the human heart is able to match ATP supply and demand perfectly. It requires 6 kg of ATP per day to satisfy demands of external work (mechanical force generation) and internal work (ion movements and basal metabolism). The heart is able to link supply with demand via direct responses to ADP and AMP concentrations but calcium concentrations within myocytes play a key role, signalling both inotropy, chronotropy and matched increases in ATP production. Calcium/calmodulin-dependent protein kinase (CaMKII) is a key adapter to increased workload, facilitating a greater and more rapid calcium concentration change. In the failing heart, this is dysfunctional and ATP supply is impaired. This review aims to examine the mechanisms and pathologies that link increased energy demand to this disrupted situation. We examine the roles of calcium loading, oxidative stress, mitochondrial structural abnormalities and damage-associated molecular patterns.
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Heart failure with preserved ejection fraction (HFpEF) is increasingly prevalent and now accounts for half of all heart failure cases. This rise is largely attributed to growing rates of obesity, hypertension, and diabetes. Despite its prevalence, the pathophysiological mechanisms of HFpEF are not fully understood. The heart, being the most energy-demanding organ, appears to have a compromised bioenergetic capacity in heart failure, affecting all phenotypes and aetiologies. While metabolic disturbances in heart failure with reduced ejection fraction (HFrEF) have been extensively studied, similar insights into HFpEF are limited. This review collates evidence from both animal and human studies, highlighting metabolic dysregulations associated with HFpEF and its risk factors, such as obesity, hypertension, and diabetes. We discuss how changes in substrate utilisation, oxidative phosphorylation, and energy transport contribute to HFpEF. By delving into these pathological shifts in myocardial energy production, we aim to reveal novel therapeutic opportunities. Potential strategies include modulating energy substrates, improving metabolic efficiency, and enhancing critical metabolic pathways. Understanding these aspects could be key to developing more effective treatments for HFpEF.
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AIMS: To conduct a meta-analysis of randomized controlled trials (RCTs) to assess the effect of sodium-glucose cotransporter-2 (SGLT2) inhibitors on inflammatory biomarkers. METHODS: Medline, Embase and the Cochrane Library were searched for RCTs investigating the effect of SGLT2 inhibitors on inflammatory biomarkers, adipokine profiles and insulin sensitivity. RESULTS: Thirty-eight RCTs were included (14 967 participants, 63.3% male, mean age 62 ± 8.6 years) with a median (interquartile range) follow-up of 16 (12-24) weeks. Meta-analysis showed that SGLT2 inhibitors significantly improved adiponectin, interleukin-6, tumour necrosis factor receptor-1 (vs. placebo alone: standardized mean difference [SMD] 0.34 [95% confidence interval {CI} 0.23, 0.45], mean difference [MD] -0.85 pg/mL [95% CI -1.32, -0.38], SMD -0.13 [95% CI -0.20, -0.06], respectively), leptin and homeostatic model assessment of insulin resistance index (vs. CONTROL: SMD -0.20 [95% CI -0.33, -0.07], MD -0.83 [95% CI -1.32, -0.33], respectively). There were no significant changes in C-reactive protein (CRP), tumour necrosis factor-α, plasminogen activator inhibitor-1, fibroblast growth factor-21 or monocyte chemoattractant protein-1. CONCLUSIONS: Our analysis shows that SGLT2 inhibitors likely improve adipokine biomarkers and insulin sensitivity, but there is little evidence that SGLT2 inhibitors improve other inflammatory biomarkers including CRP.
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Biomarcadores , Diabetes Mellitus Tipo 2 , Inflamación , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adipoquinas/sangre , Adiponectina/sangre , Biomarcadores/sangre , Proteína C-Reactiva/análisis , Proteína C-Reactiva/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/sangre , Inflamación/sangre , Resistencia a la Insulina , Interleucina-6/sangre , Interleucina-6/antagonistas & inhibidores , Leptina/sangre , Inhibidor 1 de Activador Plasminogénico/sangre , Ensayos Clínicos Controlados Aleatorios como Asunto , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacologíaRESUMEN
AIMS: The trials upon which recommendations for the use of cardiac resynchronization therapy (CRT) in heart failure used optimal medical therapy (OMT) before sodium-glucose co-transporter 2 inhibitors (SGLT2i). Moreover, the SGLT2i heart failure trials included only a small proportion of participants with CRT, and therefore, it remains uncertain whether SGLT2i should be considered part of OMT prior to CRT. METHODS AND RESULTS: We compared electrocardiogram (ECG) and echocardiographic responses to CRT as well as hospitalization and mortality rates in consecutive patients undergoing implantation at a large tertiary centre between January 2019 to June 2022 with and without SGLT2i treatment. Three hundred seventy-four participants were included aged 74.0 ± 11.5 years (mean ± standard deviation), with a left ventricular ejection fraction (LVEF) of 31.8 ± 9.9% and QRS duration of 161 ± 29 ms. The majority had non-ischaemic cardiomyopathy (58%) and were in NYHA Class II/III (83.6%). These characteristics were similar between patients with (n = 66) and without (n = 308) prior SGLT2i treatment. Both groups demonstrated similar evidence of response to CRT in terms of QRS duration shortening, and improvements in LVEF, left ventricular end-diastolic inner-dimension (LVIDd) and diastolic function (E/A and e/e'). While there was no difference in rates of hospitalization (for heart failure or overall), mortality was significantly lower in patients treated with SGLT2i compared with those who were not (6.5 vs. 16.6%, P = 0.049). CONCLUSIONS: We observed an improvement in mortality in patients undergoing CRT prescribed SGLT2i compared with those not prescribed SGLT2i, despite similar degrees of reverse remodelling. The authors recommend starting SGLT2i prior to CRT implantation, where it does not delay implantation.
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Terapia de Resincronización Cardíaca , Insuficiencia Cardíaca , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Masculino , Femenino , Terapia de Resincronización Cardíaca/métodos , Anciano , Insuficiencia Cardíaca/terapia , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/fisiopatología , Resultado del Tratamiento , Volumen Sistólico/fisiología , Estudios Retrospectivos , Función Ventricular Izquierda/fisiología , Ecocardiografía , Electrocardiografía , Estudios de Seguimiento , Tasa de Supervivencia/tendenciasRESUMEN
BACKGROUND: Since the COVID-19 pandemic, post-COVID syndrome (persistent symptoms/complications lasting >12 weeks) continues to pose medical and economic challenges. In military personnel, where optimal fitness is crucial, prolonged limitations affecting their ability to perform duties has occupational and psychological implications, impacting deployability and retention. Research investigating post-COVID syndrome exercise capacity and cardiopulmonary effects in military personnel is limited. METHODS: UK military personnel were recruited from the Defence Medical Services COVID-19 Recovery Service. Participants were separated into healthy controls without prior SARS-CoV-2 infection (group one), and participants with prolonged symptoms (>12 weeks) after mild-moderate (community-treated) and severe (hospitalised) COVID-19 illness (group 2 and 3, respectively). Participants underwent cardiac magnetic resonance imaging (CMR) and spectroscopy, echocardiography, pulmonary function testing and cardiopulmonary exercise testing (CPET). RESULTS: 113 participants were recruited. When compared in ordered groups (one to three), CPET showed stepwise decreases in peak work, work at VT1 and VO2 max (all p < 0.01). There were stepwise decreases in FVC (p = 0.002), FEV1 (p = 0.005), TLC (p = 0.002), VA (p < 0.001), and DLCO (p < 0.002), and a stepwise increase in A-a gradient (p < 0.001). CMR showed stepwise decreases in LV/RV volumes, stroke volumes and LV mass (LVEDVi/RVEDVi p < 0.001; LVSV p = 0.003; RVSV p = 0.001; LV mass index p = 0.049). CONCLUSION: In an active military population, post-COVID syndrome is linked to subclinical changes in maximal exercise capacity. Alongside disease specific changes, many of these findings share the phenotype of deconditioning following prolonged illness or bedrest. Partitioning of the relative contribution of pathological changes from COVID-19 and deconditioning is challenging in post-COVID syndrome recovery.
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COVID-19 , Personal Militar , Humanos , Tolerancia al Ejercicio , Pandemias , SARS-CoV-2 , Pulmón , Prueba de EsfuerzoRESUMEN
Aims: Left ventricular (LV) pressure-volume (PV) loops provide gold-standard physiological information but require invasive measurements of ventricular intracavity pressure, limiting clinical and research applications. A non-invasive method for the computation of PV loops from magnetic resonance imaging and brachial cuff blood pressure has recently been proposed. Here we evaluated the fidelity of the non-invasive PV algorithm against invasive LV pressures in humans. Methods and results: Four heart failure patients with EF < 35% and LV dyssynchrony underwent cardiovascular magnetic resonance (CMR) imaging and subsequent LV catheterization with sequential administration of two different intravenous metabolic substrate infusions (insulin/dextrose and lipid emulsion), producing eight datasets at different haemodynamic states. Pressure-volume loops were computed from CMR volumes combined with (i) a time-varying elastance function scaled to brachial blood pressure and temporally stretched to match volume data, or (ii) invasive pressures averaged from 19 to 30 sampled beats. Method comparison was conducted using linear regression and Bland-Altman analysis. Non-invasively derived PV loop parameters demonstrated high correlation and low bias when compared to invasive data for stroke work (R2 = 0.96, P < 0.0001, bias 4.6%), potential energy (R2 = 0.83, P = 0.001, bias 1.5%), end-systolic pressure-volume relationship (R2 = 0.89, P = 0.0004, bias 5.8%), ventricular efficiency (R2 = 0.98, P < 0.0001, bias 0.8%), arterial elastance (R2 = 0.88, P = 0.0006, bias -8.0%), mean external power (R2 = 0.92, P = 0.0002, bias 4.4%), and energy per ejected volume (R2 = 0.89, P = 0.0001, bias 3.7%). Variations in estimated end-diastolic pressure did not significantly affect results (P > 0.05 for all). Intraobserver analysis after one year demonstrated 0.9-3.4% bias for LV volumetry and 0.2-5.4% for PV loop-derived parameters. Conclusion: Pressure-volume loops can be precisely and accurately computed from CMR imaging and brachial cuff blood pressure in humans.
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BACKGROUND: Severe aortic stenosis (AS) is associated with left ventricular (LV) hypertrophy and cardiac metabolic alterations with evidence of steatosis and impaired myocardial energetics. Despite this common phenotype, there is an unexplained and wide individual heterogeneity in the degree of hypertrophy and progression to myocardial fibrosis and heart failure. We sought to determine whether the cardiac metabolic state may underpin this variability. METHODS: We recruited 74 asymptomatic participants with AS and 13 healthy volunteers. Cardiac energetics were measured using phosphorus spectroscopy to define the myocardial phosphocreatine to adenosine triphosphate ratio. Myocardial lipid content was determined using proton spectroscopy. Cardiac function was assessed by cardiovascular magnetic resonance cine imaging. RESULTS: Phosphocreatine/adenosine triphosphate was reduced early and significantly across the LV wall thickness quartiles (Q2, 1.50 [1.21-1.71] versus Q1, 1.64 [1.53-1.94]) with a progressive decline with increasing disease severity (Q4, 1.48 [1.18-1.70]; P=0.02). Myocardial triglyceride content levels were overall higher in all the quartiles with a significant increase seen across the AV pressure gradient quartiles (Q2, 1.36 [0.86-1.98] versus Q1, 1.03 [0.81-1.56]; P=0.034). While all AS groups had evidence of subclinical LV dysfunction with impaired strain parameters, impaired systolic longitudinal strain was related to the degree of energetic impairment (r=0.219; P=0.03). Phosphocreatine/adenosine triphosphate was not only an independent predictor of LV wall thickness (r=-0.20; P=0.04) but also strongly associated with myocardial fibrosis (r=-0.24; P=0.03), suggesting that metabolic changes play a role in disease progression. The metabolic and functional parameters showed comparable results when graded by clinical severity of AS. CONCLUSIONS: A gradient of myocardial energetic deficit and steatosis exists across the spectrum of hypertrophied AS hearts, and these metabolic changes precede irreversible LV remodeling and subclinical dysfunction. As such, cardiac metabolism may play an important and potentially causal role in disease progression.
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Estenosis de la Válvula Aórtica , Cardiomiopatías , Humanos , Fosfocreatina/metabolismo , Hipertrofia Ventricular Izquierda/diagnóstico por imagen , Hipertrofia Ventricular Izquierda/etiología , Hipertrofia Ventricular Izquierda/metabolismo , Estenosis de la Válvula Aórtica/diagnóstico por imagen , Estenosis de la Válvula Aórtica/complicaciones , Adenosina Trifosfato/metabolismo , Cardiomiopatías/complicaciones , Fibrosis , Fenotipo , Progresión de la Enfermedad , Función Ventricular IzquierdaRESUMEN
BACKGROUND: Type 2 diabetes (T2D) is associated with an increased risk of left ventricular dysfunction after aortic valve replacement (AVR) in patients with severe aortic stenosis (AS). Persistent impairments in myocardial energetics and myocardial blood flow (MBF) may underpin this observation. Using phosphorus magnetic resonance spectroscopy and cardiovascular magnetic resonance, this study tested the hypothesis that patients with severe AS and T2D (AS-T2D) would have impaired myocardial energetics as reflected by the phosphocreatine to ATP ratio (PCr/ATP) and vasodilator stress MBF compared with patients with AS without T2D (AS-noT2D), and that these differences would persist after AVR. METHODS: Ninety-five patients with severe AS without coronary artery disease awaiting AVR (30 AS-T2D and 65 AS-noT2D) were recruited (mean, 71 years of age [95% CI, 69, 73]; 34 [37%] women). Thirty demographically matched healthy volunteers (HVs) and 30 patients with T2D without AS (T2D controls) were controls. One month before and 6 months after AVR, cardiac PCr/ATP, adenosine stress MBF, global longitudinal strain, NT-proBNP (N-terminal pro-B-type natriuretic peptide), and 6-minute walk distance were assessed in patients with AS. T2D controls underwent identical assessments at baseline and 6-month follow-up. HVs were assessed once and did not undergo 6-minute walk testing. RESULTS: Compared with HVs, patients with AS (AS-T2D and AS-noT2D combined) showed impairment in PCr/ATP (mean [95% CI]; HVs, 2.15 [1.89, 2.34]; AS, 1.66 [1.56, 1.75]; P<0.0001) and vasodilator stress MBF (HVs, 2.11 mL min g [1.89, 2.34]; AS, 1.54 mL min g [1.41, 1.66]; P<0.0001) before AVR. Before AVR, within the AS group, patients with AS-T2D had worse PCr/ATP (AS-noT2D, 1.74 [1.62, 1.86]; AS-T2D, 1.44 [1.32, 1.56]; P=0.002) and vasodilator stress MBF (AS-noT2D, 1.67 mL min g [1.5, 1.84]; AS-T2D, 1.25 mL min g [1.22, 1.38]; P=0.001) compared with patients with AS-noT2D. Before AVR, patients with AS-T2D also had worse PCr/ATP (AS-T2D, 1.44 [1.30, 1.60]; T2D controls, 1.66 [1.56, 1.75]; P=0.04) and vasodilator stress MBF (AS-T2D, 1.25 mL min g [1.10, 1.41]; T2D controls, 1.54 mL min g [1.41, 1.66]; P=0.001) compared with T2D controls at baseline. After AVR, PCr/ATP normalized in patients with AS-noT2D, whereas patients with AS-T2D showed no improvements (AS-noT2D, 2.11 [1.79, 2.43]; AS-T2D, 1.30 [1.07, 1.53]; P=0.0006). Vasodilator stress MBF improved in both AS groups after AVR, but this remained lower in patients with AS-T2D (AS-noT2D, 1.80 mL min g [1.59, 2.0]; AS-T2D, 1.48 mL min g [1.29, 1.66]; P=0.03). There were no longer differences in PCr/ATP (AS-T2D, 1.44 [1.30, 1.60]; T2D controls, 1.51 [1.34, 1.53]; P=0.12) or vasodilator stress MBF (AS-T2D, 1.48 mL min g [1.29, 1.66]; T2D controls, 1.60 mL min g [1.34, 1.86]; P=0.82) between patients with AS-T2D after AVR and T2D controls at follow-up. Whereas global longitudinal strain, 6-minute walk distance, and NT-proBNP all improved after AVR in patients with AS-noT2D, no improvement in these assessments was observed in patients with AS-T2D. CONCLUSIONS: Among patients with severe AS, those with T2D demonstrate persistent abnormalities in myocardial PCr/ATP, vasodilator stress MBF, and cardiac contractile function after AVR; AVR effectively normalizes myocardial PCr/ATP, vasodilator stress MBF, and cardiac contractile function in patients without T2D.
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Estenosis de la Válvula Aórtica , Diabetes Mellitus Tipo 2 , Implantación de Prótesis de Válvulas Cardíacas , Humanos , Femenino , Masculino , Válvula Aórtica/diagnóstico por imagen , Válvula Aórtica/cirugía , Diabetes Mellitus Tipo 2/complicaciones , Función Ventricular Izquierda/fisiología , Vasodilatadores , Adenosina Trifosfato , Implantación de Prótesis de Válvulas Cardíacas/efectos adversosRESUMEN
Heart failure demographics have evolved in past decades with the development of improved diagnostics, therapies, and prevention. Cardiac magnetic resonance (CMR) has developed in a similar timeframe to become the gold-standard non-invasive imaging modality for characterizing diseases causing heart failure. CMR techniques to assess cardiac morphology and function have progressed since their first use in the 1980s. Increasingly efficient acquisition protocols generate high spatial and temporal resolution images in less time. This has enabled new methods of characterizing cardiac systolic and diastolic function such as strain analysis, exercise real-time cine imaging and four-dimensional flow. A key strength of CMR is its ability to non-invasively interrogate the myocardial tissue composition. Gadolinium contrast agents revolutionized non-invasive cardiac imaging with the late gadolinium enhancement technique. Further advances enabled quantitative parametric mapping to increase sensitivity at detecting diffuse pathology. Novel methods such as diffusion tensor imaging and artificial intelligence-enhanced image generation are on the horizon. Magnetic resonance spectroscopy (MRS) provides a window into the molecular environment of the myocardium. Phosphorus (31P) spectroscopy can inform the status of cardiac energetics in health and disease. Proton (1H) spectroscopy complements this by measuring creatine and intramyocardial lipids. Hyperpolarized carbon (13C) spectroscopy is a novel method that could further our understanding of dynamic cardiac metabolism. CMR of other organs such as the lungs may add further depth into phenotypes of heart failure. The vast capabilities of CMR should be deployed and interpreted in context of current heart failure challenges.
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Medios de Contraste , Insuficiencia Cardíaca , Humanos , Inteligencia Artificial , Imagen de Difusión Tensora , Gadolinio , Insuficiencia Cardíaca/diagnóstico por imagen , Insuficiencia Cardíaca/patología , Imagen por Resonancia Magnética , Imagen por Resonancia Cinemagnética/métodos , Miocardio/patología , Valor Predictivo de las PruebasRESUMEN
BACKGROUND: The failing heart is traditionally described as metabolically inflexible and oxygen starved, causing energetic deficit and contractile dysfunction. Current metabolic modulator therapies aim to increase glucose oxidation to increase oxygen efficiency of adenosine triphosphate production, with mixed results. METHODS: To investigate metabolic flexibility and oxygen delivery in the failing heart, 20 patients with nonischemic heart failure with reduced ejection fraction (left ventricular ejection fraction 34.9±9.1) underwent separate infusions of insulin+glucose infusion (I+G) or Intralipid infusion. We used cardiovascular magnetic resonance to assess cardiac function and measured energetics using phosphorus-31 magnetic resonance spectroscopy. To investigate the effects of these infusions on cardiac substrate use, function, and myocardial oxygen uptake (MVo2), invasive arteriovenous sampling and pressure-volume loops were performed (n=9). RESULTS: At rest, we found that the heart had considerable metabolic flexibility. During I+G, cardiac glucose uptake and oxidation were predominant (70±14% total energy substrate for adenosine triphosphate production versus 17±16% for Intralipid; P=0.002); however, no change in cardiac function was seen relative to basal conditions. In contrast, during Intralipid infusion, cardiac long-chain fatty acid (LCFA) delivery, uptake, LCFA acylcarnitine production, and fatty acid oxidation were all increased (LCFA 73±17% of total substrate versus 19±26% total during I+G; P=0.009). Myocardial energetics were better with Intralipid compared with I+G (phosphocreatine/adenosine triphosphate 1.86±0.25 versus 2.01±0.33; P=0.02), and systolic and diastolic function were improved (LVEF 34.9±9.1 baseline, 33.7±8.2 I+G, 39.9±9.3 Intralipid; P<0.001). During increased cardiac workload, LCFA uptake and oxidation were again increased during both infusions. There was no evidence of systolic dysfunction or lactate efflux at 65% maximal heart rate, suggesting that a metabolic switch to fat did not cause clinically meaningful ischemic metabolism. CONCLUSIONS: Our findings show that even in nonischemic heart failure with reduced ejection fraction with severely impaired systolic function, significant cardiac metabolic flexibility is retained, including the ability to alter substrate use to match both arterial supply and changes in workload. Increasing LCFA uptake and oxidation is associated with improved myocardial energetics and contractility. Together, these findings challenge aspects of the rationale underlying existing metabolic therapies for heart failure and suggest that strategies promoting fatty acid oxidation may form the basis for future therapies.
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Insuficiencia Cardíaca , Disfunción Ventricular Izquierda , Humanos , Volumen Sistólico , Metabolismo Energético , Función Ventricular Izquierda , Miocardio/metabolismo , Insuficiencia Cardíaca/patología , Adenosina Trifosfato/metabolismo , Disfunción Ventricular Izquierda/patología , Ácidos Grasos/metabolismo , Glucosa/metabolismo , Oxígeno/metabolismoRESUMEN
BACKGROUND: Sodium-glucose co-transporter 2 inhibitors (SGLT2i) have emerged as a paramount treatment for patients with heart failure (HF), irrespective of underlying reduced or preserved ejection fraction. However, a definite cardiac mechanism of action remains elusive. Derangements in myocardial energy metabolism are detectable in all HF phenotypes, and it was proposed that SGLT2i may improve energy production. The authors aimed to investigate whether treatment with empagliflozin leads to changes in myocardial energetics, serum metabolomics, and cardiorespiratory fitness. METHODS: EMPA-VISION (Assessment of Cardiac Energy Metabolism, Function and Physiology in Patients With Heart Failure Taking Empagliflozin) is a prospective, randomized, double-blind, placebo-controlled, mechanistic trial that enrolled 72 symptomatic patients with chronic HF with reduced ejection fraction (HFrEF; n=36; left ventricular ejection fraction ≤40%; New York Heart Association class ≥II; NT-proBNP [N-terminal pro-B-type natriuretic peptide] ≥125 pg/mL) and HF with preserved ejection fraction (HFpEF; n=36; left ventricular ejection fraction ≥50%; New York Heart Association class ≥II; NT-proBNP ≥125 pg/mL). Patients were stratified into respective cohorts (HFrEF versus HFpEF) and randomly assigned to empagliflozin (10 mg; n=35: 17 HFrEF and 18 HFpEF) or placebo (n=37: 19 HFrEF and 18 HFpEF) once daily for 12 weeks. The primary end point was a change in the cardiac phosphocreatine:ATP ratio (PCr/ATP) from baseline to week 12, determined by phosphorus magnetic resonance spectroscopy at rest and during peak dobutamine stress (65% of age-maximum heart rate). Mass spectrometry on a targeted set of 19 metabolites was performed at baseline and after treatment. Other exploratory end points were investigated. RESULTS: Empagliflozin treatment did not change cardiac energetics (ie, PCr/ATP) at rest in HFrEF (adjusted mean treatment difference [empagliflozin - placebo], -0.25 [95% CI, -0.58 to 0.09]; P=0.14) or HFpEF (adjusted mean treatment difference, -0.16 [95% CI, -0.60 to 0.29]; P=0.47]. Likewise, there were no changes in PCr/ATP during dobutamine stress in HFrEF (adjusted mean treatment difference, -0.13 [95% CI, -0.35 to 0.09]; P=0.23) or HFpEF (adjusted mean treatment difference, -0.22 [95% CI, -0.66 to 0.23]; P=0.32). No changes in serum metabolomics or levels of circulating ketone bodies were observed. CONCLUSIONS: In patients with either HFrEF or HFpEF, treatment with 10 mg of empagliflozin once daily for 12 weeks did not improve cardiac energetics or change circulating serum metabolites associated with energy metabolism when compared with placebo. Based on our results, it is unlikely that enhancing cardiac energy metabolism mediates the beneficial effects of SGLT2i in HF. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03332212.
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Insuficiencia Cardíaca , Humanos , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/tratamiento farmacológico , Volumen Sistólico , Función Ventricular Izquierda , Estudios Prospectivos , Dobutamina/farmacología , Metabolismo Energético , Adenosina TrifosfatoRESUMEN
Humans have a larger energy budget than great apes, allowing the combination of the metabolically expensive traits that define our life history. This budget is ultimately related to the cardiac output, the product of the blood pumped from the ventricle and the number of heart beats per minute, a measure of the blood available for the whole organism physiological activity. To show the relationship between cardiac output and energy expenditure in hominid evolution, we study a surrogate measure of cardiac output, the aortic root diameter, in humans and great apes. When compared to gorillas and chimpanzees, humans present an increased body mass adjusted aortic root diameter. We also use data from the literature to show that over the human lifespan, cardiac output and total energy expenditure follow almost identical trajectories, with a marked increase during the period of brain growth, and a plateau during most of the adult life. The limited variation of adjusted cardiac output with sex, age and physical activity supports the compensation model of energy expenditure in humans. Finally, we present a first study of cardiac output in the skeleton through the study of the aortic impression in the vertebral bodies of the spine. It is absent in great apes, and present in humans and Neanderthals, large-brained hominins with an extended life cycle. An increased adjusted cardiac output, underlying higher total energy expenditure, would have been a key process in human evolution.
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Hominidae , Hombre de Neandertal , Adulto , Animales , Humanos , Hominidae/fisiología , Gorilla gorilla , Pan troglodytes , Aorta , Gasto Cardíaco , Evolución BiológicaRESUMEN
PURPOSE OF REVIEW: Myocardial metabolism is intricately linked to cardiac function. Perturbations of cardiac energy metabolism result in an energy-starved heart and the development of contractile dysfunction. In this review, we discuss alterations in myocardial energy supply, transcriptional changes in response to different energy demands, and mitochondrial function in the development of heart failure. RECENT FINDINGS: Recent studies on substrate modulation through modifying energy substrate supply have shown cardioprotective properties. In addition, large cardiovascular outcome trials of anti-diabetic agents have demonstrated prognostic benefit, suggesting the importance of myocardial metabolism in cardiac function. Understanding molecular and transcriptional controls of cardiac metabolism promises new research avenues for metabolic treatment targets. Future studies assessing the impact of substrate modulation on cardiac energetic status and function will better inform development of metabolic therapies.
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Insuficiencia Cardíaca , Humanos , Miocardio/metabolismo , Metabolismo Energético , Hipoglucemiantes , CorazónRESUMEN
BACKGROUND: The COVID-19 pandemic has led to significant morbidity and mortality, with the former impacting and limiting individuals requiring high physical fitness, including sportspeople and emergency services. METHODS: Observational cohort study of 4 groups: hospitalised, community illness with on-going symptoms (community-symptomatic), community illness now recovered (community-recovered) and comparison. A total of 113 participants (aged 39 ± 9, 86% male) were recruited: hospitalised (n = 35), community-symptomatic (n = 34), community-recovered (n = 18) and comparison (n = 26), approximately five months following acute illness. Participant outcome measures included cardiopulmonary imaging, submaximal and maximal exercise testing, pulmonary function, cognitive assessment, blood tests and questionnaires on mental health and function. RESULTS: Hospitalised and community-symptomatic groups were older (43 ± 9 and 37 ± 10, P = 0.003), with a higher body mass index (31 ± 4 and 29 ± 4, P < 0.001), and had worse mental health (anxiety, depression and post-traumatic stress), fatigue and quality of life scores. Hospitalised and community-symptomatic participants performed less well on sub-maximal and maximal exercise testing. Hospitalised individuals had impaired ventilatory efficiency (higher VE/VÌCO2 slope, 29.6 ± 5.1, P < 0.001), achieved less work at anaerobic threshold (70 ± 15, P < 0.001) and peak (231 ± 35, P < 0.001), and had a reduced forced vital capacity (4.7 ± 0.9, P = 0.004). Clinically significant abnormal cardiopulmonary imaging findings were present in 6% of hospitalised participants. Community-recovered individuals had no significant differences in outcomes to the comparison group. CONCLUSION: Symptomatically recovered individuals who suffered mild-moderate acute COVID-19 do not differ from an age-, sex- and job-role-matched comparison population five months post-illness. Individuals who were hospitalised or continue to suffer symptoms may require a specific comprehensive assessment prior to return to full physical activity.
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AIMS: We examined associations of obesity with incident cardiovascular outcomes and cardiovascular magnetic resonance (CMR) phenotypes, integrating information from body mass index (BMI) and waist-to-hip ratio (WHR). Then, we used multiple mediation to define the role of obesity-related cardiac remodelling in driving obesity-outcome associations, independent of cardiometabolic diseases. METHODS AND RESULTS: In 491 606 UK Biobank participants, using Cox proportional hazard models, greater obesity (higher WHR, higher BMI) was linked to significantly greater risk of incident ischaemic heart disease, atrial fibrillation (AF), heart failure (HF), all-cause mortality, and cardiovascular disease (CVD) mortality. In combined stratification by BMI and WHR thresholds, elevated WHR was associated with greater risk of adverse outcomes at any BMI level. Individuals with overweight BMI but normal WHR had weaker disease associations. In the subset of participants with CMR (n = 31 107), using linear regression, greater obesity was associated with higher left ventricular (LV) mass, greater LV concentricity, poorer LV systolic function, lower myocardial native T1, larger left atrial (LA) volumes, poorer LA function, and lower aortic distensibility. Of note, higher BMI was linked to higher, whilst greater WHR was linked to lower LV end-diastolic volume (LVEDV). In Cox models, greater LVEDV and LV mass (LVM) were linked to increased risk of CVD, most importantly HF and an increased LA maximal volume was the key predictive measure of new-onset AF. In multiple mediation analyses, hypertension and adverse LV remodelling (higher LVM, greater concentricity) were major independent mediators of the obesity-outcome associations. Atrial remodelling and native T1 were additional mediators in the associations of obesity with AF and HF, respectively. CONCLUSIONS: We demonstrate associations of obesity with adverse cardiovascular phenotypes and their significant independent role in mediating obesity-outcome relationships. In addition, our findings support the integrated use of BMI and WHR to evaluate obesity-related cardiovascular risk.
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Enfermedades Cardiovasculares , Sistema Cardiovascular , Insuficiencia Cardíaca , Humanos , Obesidad/complicaciones , Enfermedades Cardiovasculares/diagnóstico por imagen , Enfermedades Cardiovasculares/epidemiología , Relación Cintura-Cadera , Índice de Masa Corporal , Factores de RiesgoRESUMEN
Obesity and heart failure with preserved ejection fraction (HFpEF) represent two intermingling epidemics driving perhaps the greatest unmet health problem in cardiovascular medicine in the 21st century. Many patients with HFpEF are either overweight or obese, and recent data have shown that increased body fat and its attendant metabolic sequelae have widespread, protean effects systemically and on the cardiovascular system leading to symptomatic HFpEF. The paucity of effective therapies in HFpEF underscores the importance of understanding the distinct pathophysiological mechanisms of obese HFpEF to develop novel therapies. In this review, we summarize the current understanding of the cardiovascular and non-cardiovascular features of the obese phenotype of HFpEF, how increased adiposity might pathophysiologically contribute to the phenotype, and how these processes might be targeted therapeutically.
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Insuficiencia Cardíaca , Humanos , Volumen Sistólico/fisiología , Corazón , Obesidad , AdiposidadRESUMEN
Motivation: 31P magnetic resonance spectroscopic imaging (31P MRSI) is a powerful technique for investigating the metabolic effects of treatments for heart failure in vivo, allowing a better understanding of their mechanism of action in patient cohorts. Unfortunately, cardiac 31P MRSI is fundamentally limited by low SNR, which leads to compromises in acquisition, such as no cardiac or respiratory gating or low spatial resolution, in order to achieve reasonable scan times. Spectroscopy with linear algebra modeling (SLAM) reconstruction may be able to address these challenges and therefore improve repeatability by incorporating a segmented localizer into the reconstruction. Methods: Six healthy volunteers were scanned twice in a test-retest procedure to allow quantification of repeatability. Each scan consisted of anatomical localizers and two acquisition-weighted (AW) 31P MRSI acquisitions, which were acquired with and without cardiac gating. Five patients with heart failure with a preserved ejection fraction were then scanned with the same 31P MRSI sequence without cardiac gating. All 31P MRSI datasets were reconstructed with both conventional Fourier transform (FT)-based reconstruction and SLAM reconstruction, which were compared statistically. The effect of shifting the 31P MRSI acquisition field of view was also investigated. Results: In the healthy volunteer cohort, the spectral fit of the SLAM reconstructions had significantly improved Cramer-Rao lower bounds (CRLBs) compared to the FT-based reconstruction of non-cardiac gated data, as well as improved coefficients of variability and repeatability. The SLAM reconstruction found a significant difference in the PCr/ATP ratio between the healthy volunteer and patient cohorts, which the FT-based reconstruction did not find. Furthermore, the SLAM reconstruction was less influenced by the placement of the field of view (FOV) of the 31P MRSI acquisition in post hoc analysis. Discussion: The experimental benefits of the SLAM reconstruction for AW data were demonstrated by the improvements in fit confidence and repeatability seen in the healthy volunteer cohort and post hoc FOV analysis. The benefit of SLAM reconstruction of AW data for clinical studies was then illustrated by the patient cohort, which suggested improved sensitivity to clinically significant changes in the PCr/ATP ratio.
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Pressure overload in aortic stenosis (AS) encompasses both structural and metabolic remodeling and increases the risk of decompensation into heart failure. A major component of metabolic derangement in AS is abnormal cardiac substrate use, with down-regulation of fatty acid oxidation, increased reliance on glucose metabolism, and subsequent myocardial lipid accumulation. These changes are associated with energetic and functional cardiac impairment in AS and can be assessed with the use of cardiac magnetic resonance spectroscopy (MRS). Proton MRS allows the assessment of myocardial triglyceride content and creatine concentration. Phosphorous MRS allows noninvasive in vivo quantification of the phosphocreatine-to-adenosine triphosphate ratio, a measure of cardiac energy status that is reduced in patients with severe AS. This review summarizes the changes to cardiac substrate and high-energy phosphorous metabolism and how they affect cardiac function in AS. The authors focus on the role of MRS to assess these metabolic changes, and potentially guide future (cellular) metabolic therapy in AS.