Aksentijevic D, Sedej S, Fauconnier J
… +10 more, Paillard M, Abdellatif M, Streckfuss-Bömeke K, Ventura-Clapier R, van der Velden J, de Boer RA, Bertero E, Dudek J, Sequeira V, Maack C
Heart failure (HF) is a major global and life-threatening disease. Despite advances in therapies, the prevalence of HF is increasing owing to an ageing population and the pervasive pandemic of obesity and metabolic disor...Heart failure (HF) is a major global and life-threatening disease. Despite advances in therapies, the prevalence of HF is increasing owing to an ageing population and the pervasive pandemic of obesity and metabolic disorders, which have transformed the pathophysiology of HF. Changes in cardiac energy metabolism and the related energy deficit crucially contribute to the severity and type of HF. Furthermore, perturbations in excitation-contraction coupling, mitochondrial function and oxidative stress are characteristic features of HF. In this Review, we focus on the close interaction between cardiac mechanics and mitochondrial energetics, and decipher how this mechano-energetic coupling is disturbed in various acquired and hereditary forms of HF. In HF with reduced ejection fraction, defects in excitation-contraction coupling are key drivers of mechano-energetic uncoupling, whereas in HF with preserved ejection fraction, increased preload and afterload imposed by obesity, hypertension and age-dependent vascular stiffness increase mechanical workload, which is insufficiently matched by mitochondrial tricarboxylic acid cycle activity and ATP supply. In both scenarios, oxidative stress results from depletion of the antioxidative capacity and contributes to maladaptive cardiac remodelling and dysfunction. Several established and emerging treatments for HF target this mechano-energetic uncoupling, and a greater understanding of the underlying mechanisms will open new therapeutic opportunities to alleviate the burden of HF.
Glycogen storage diseases are rare conditions affecting both sexes that are caused by inherited deficiencies of enzymes involved either in glycogen synthesis or breakdown, or in glycolysis. The liver and skeletal muscle...Glycogen storage diseases are rare conditions affecting both sexes that are caused by inherited deficiencies of enzymes involved either in glycogen synthesis or breakdown, or in glycolysis. The liver and skeletal muscle are usually the most affected tissues. However, because glycogen has an important role in cardiac development and function, several glycogen storage diseases are associated, at least indirectly, with cardiac disorders, some of which have severe consequences from the first months of life. Early identification of these conditions is, therefore, an important issue, and implementation of strategies to prevent fatal outcomes due to cardiovascular disease is vital. In this Review, we discuss the pathophysiological mechanisms and the preclinical, clinical and epidemiological evidence for cardiovascular involvement in various glycogen storage diseases. We also describe interventions that can help preserve heart function, including changes in nutrition and exercise, as well as the few available molecular therapies to address the underlying metabolic anomalies.
Cardiovascular diseases are the leading cause of death globally, with cardiac arrhythmias contributing substantially to this burden. Gene therapy, which directly targets the underlying disease pathobiology, offers an app...Cardiovascular diseases are the leading cause of death globally, with cardiac arrhythmias contributing substantially to this burden. Gene therapy, which directly targets the underlying disease pathobiology, offers an appealing treatment strategy for cardiac arrhythmias owing to its potential as a one-time, curative solution. Over the past two decades, substantial efforts have been made to develop new gene therapy approaches that overcome the limitations of conventional treatments. In this Review, we describe the rationale for gene therapy to treat cardiac arrhythmias; discuss advantages and disadvantages of gene silencing, gene replacement, gene suppression-and-replacement and gene editing technologies; summarize vector modalities and delivery approaches used in the field; present examples of gene therapy strategies used for atrial and ventricular arrhythmias; and highlight the current challenges and limitations in the gene therapy field.
Endothelial cells are multifunctional cells that form the inner layer of blood vessels and have a crucial role in vasoreactivity, angiogenesis, immunomodulation, nutrient uptake and coagulation. Endothelial cells have un...Endothelial cells are multifunctional cells that form the inner layer of blood vessels and have a crucial role in vasoreactivity, angiogenesis, immunomodulation, nutrient uptake and coagulation. Endothelial cells have unique metabolism and are metabolically heterogeneous. The microenvironment and metabolism of endothelial cells contribute to endothelial cell heterogeneity and metabolic specialization. Endothelial cell dysfunction is an early event in the development of several cardiovascular diseases and has been shown, at least to some extent, to be driven by metabolic changes preceding the manifestation of clinical symptoms. Diabetes mellitus, hypertension, obesity and chronic kidney disease are all risk factors for cardiovascular disease. Changes in endothelial cell metabolism induced by these cardiometabolic stressors accelerate the accumulation of dysfunctional endothelial cells in tissues and the development of cardiovascular disease. In this Review, we discuss the diversity of metabolic programmes that control endothelial cell function in the cardiovascular system and how these metabolic programmes are perturbed in different cardiovascular diseases in a disease-specific manner. Finally, we discuss the potential and challenges of targeting endothelial cell metabolism for the treatment of cardiovascular diseases.
The variation of heart rate in phase with breathing, known as 'respiratory sinus arrhythmia' (RSA), is a physiological phenomenon present in all air-breathing vertebrates. RSA arises from the interaction of several physi...The variation of heart rate in phase with breathing, known as 'respiratory sinus arrhythmia' (RSA), is a physiological phenomenon present in all air-breathing vertebrates. RSA arises from the interaction of several physiological mechanisms but is primarily mediated by rhythmic changes in cardiac parasympathetic (vagal) activity, increasing heart rate during inspiration and decreasing heart rate during expiration. RSA amplitude is an indicator of autonomic and cardiac health; RSA is diminished or absent in common pathological conditions such as chronic heart failure and hypertension. In this Expert Recommendation, we argue that the term 'RSA', although historically important, is semantically inaccurate and carries misleading pathological connotations, contributing to misunderstanding and misinterpretation of the origin and the physiological importance of the phenomenon. We propose replacing 'RSA' with the term 'respiratory heart rate variability' (RespHRV), which avoids pathological connotations and emphasizes the specific respiratory contribution to heart rate variability. We clarify that RespHRV encompasses respiratory-related heart rate variations in both the low-frequency and high-frequency bands traditionally defined in heart rate variability analysis, and that its amplitude should not be misconstrued as a measure of vagal tone. Adopting the proposed term 'RespHRV' is expected to unify understanding and stimulate further experimental and clinical research into the physiological mechanisms and functional importance of this phenomenon.
Heart failure is a leading cause of hospitalization worldwide, and congestion is the predominant cause of heart failure symptoms and hospitalization. The primary therapy used to treat and prevent congestion has historica...Heart failure is a leading cause of hospitalization worldwide, and congestion is the predominant cause of heart failure symptoms and hospitalization. The primary therapy used to treat and prevent congestion has historically been loop diuretics. However, many patients are discharged from hospital with residual congestion, which is associated with persistent heart failure symptoms, adverse outcomes and hospital readmission. Multiple medical strategies and devices have been and are being investigated with the aim of improving decongestion and subsequent heart failure outcomes. Numerous questions exist about the design of clinical trials to test emerging medical and device therapies, including the magnitude of benefit on congestive, kidney and post-discharge outcomes relative to conventional decongestion practices, and how best to implement novel therapies. In this Review, we discuss emerging medical and device strategies targeting congestion in patients with heart failure.