Heart failure (HF) is associated with significant morbidity and mortality. The disease is characterised by autonomic imbalance with increased sympathetic activity and withdrawal of parasympathetic ...activity. Despite the use of medical therapies that target, in part, the neurohormonal axis, rates of HF progression, morbidity and mortality remain high. Emerging therapies centred on neuromodulation of autonomic control of the heart provide an alternative device-based approach to restoring sympathovagal balance. Preclinical studies have proven favourable, while clinical trials have had mixed results. This article highlights the importance of understanding structural/functional organisation of the cardiac nervous system as mechanistic-based neuromodulation therapies evolve.
Heart failure (HF) is a complex disease with a growing incidence worldwide. HF is accompanied by a wide range of conditions which affect disease progression, functional performance and contribute to ...growing healthcare costs. The interactions between a failing myocardium and altered cerebral functions contribute to the symptoms experienced by patients with HF, affecting many comorbidities and causing a poor prognosis. This article provides a condensed version of the 2018 position paper from the Study Group on Heart and Brain Interaction of the Heart Failure Association. It addresses the reciprocal impact on HF of several pathological brain conditions, including acute and chronic low perfusion of the brain, and impairment of higher cortical and brain stem functions. Treatment-related interactions - medical, interventional and device-related - are also discussed.
Attempts have been made to assess and measure ventricular contractility in patients and whether it can be used to identify heart failure. Due to the assumption that if the contractility of all the ...muscle fibres in a heart were lower, could it be called heart failure? Early attempts involved the assumption of a model of muscle that had a contractile unit in series with an elastic element, but this was found to be incorrect. Further attempts applied the series elastic model but this model also proved challenging. However, one method has assessed changes in contractility in a given patient, in response to an intervention, but could not compare contractility in a patient with heart failure with a normal person. End-systolic pressure-volume (ESPV) is regarded as a more correct index of contractility and this method was used to confirm changes in contractility from beat to beat during AF, showing results that end-systolic volume varied and indicating a shift of ESPV from beat to beat. This review will discuss the difficulty in measurement, the complicated nature of myocardial fibre orientation and hypertrophy, and whether myocardial contractility failure precipitates increased global heart failure.
Measures of interaction between the left ventricle (LV) and arterial system (ventricular-arterial coupling) are important but under-recognised cardiovascular phenotypes in heart failure. ...Ventriculo-arterial coupling is commonly assessed in the pressure-volume plane, using the ratio of effective arterial elastance (E
) to LV end-systolic elastance (E
) to provide information on ventricular-arterial system mechanical efficiency and performance when LV ejection fraction is abnormal. These analyses have significant limitations, such as neglecting systolic loading sequence, and are less informative in heart failure with preserved ejection fraction (HFpEF). E
is almost entirely dependent on vascular resistance and heart rate. Assessment of pulsatile arterial haemodynamics and time-resolved myocardial wall stress provide critical incremental physiological information and should be more widely utilised. Pulsatile arterial load represents a promising therapeutic target in HFpEF. Here, we review various approaches to assess ventricular-arterial interactions, and their pathophysiological and clinical implications in heart failure.
Activation of the neuro-hormonal system is a pathophysiological consequence of heart failure. Neuro-hormonal activation promotes metabolic changes, such as insulin resistance, and determines an ...increased use of non-carbohydrate substrates for energy production. Fasting blood ketone bodies as well as fat oxidation are increased in patients with heart failure, yielding a state of metabolic inefficiency. The net result is additional depletion of myocardial adenosine triphosphate, phosphocreatine and creatine kinase levels with further decreased efficiency of mechanical work. In this context, manipulation of cardiac energy metabolism by modification of substrate use by the failing heart has produced positive clinical results. The results of current research support the concept that shifting the energy substrate preference away from fatty acid metabolism and towards glucose metabolism could be an effective adjunctive treatment in patients with heart failure. The additional use of drugs able to partially inhibit fatty acids oxidation in patients with heart failure may therefore yield a significant protective effect for clinical symptoms and cardiac function improvement, and simultaneously ameliorate left ventricular remodelling. Certainly, to clarify the exact therapeutic role of metabolic therapy in heart failure, a large multicentre, randomised controlled trial should be performed.
Natriuretic peptides play a crucial role in maintaining cardiovascular homeostasis. Among their properties are vasodilation, natriuresis, diuresis, and inhibition of cardiac remodeling. As heart ...failure progresses, however, natriuretic peptides fail to compensate. Knowledge of their processing and signaling pathways has guided the development of pharmacological therapies aimed at bolstering their effects. The drugs that have achieved the most clinical success have also stirred the most controversy. Nesiritide, the synthetic B-type natriuretic peptide, yielded significant symptomatic relief and improved haemodynamics but its use was plagued with questions surrounding its possibly harmful impact on renal function. More recently, compounds containing inhibitors of neprilysin, the enzyme responsible for degrading natriuretic peptides, have demonstrated morbidity and mortality benefit, but have also been linked to possible negative side effects. Clearly, potentiating the actions of natriuretic peptides for the benefit of patients is not as simple as just raising their serum concentration. This article reviews the current understanding of the compensatory actions of cardiac natriuretic peptides in heart failure and how this knowledge is revolutionizing heart failure therapy.
Idiopathic trigeminal neuralgia (TN) is a debilitating pain disorder characterized by episodic unilateral facial pain along the territory of branches of the trigeminal nerve. Human painful disorders, ...but not TN, have been linked to gain-of-function mutations in peripheral voltage-gated sodium channels (Na
1.7, Na
1.8 and Na
1.9). Gain-of-function mutations in Na
1.6, which is expressed in myelinated and unmyelinated CNS and peripheral nervous system neurons and supports neuronal high-frequency firing, have been linked to epilepsy but not to pain. Here, we describe an individual who presented with evoked and spontaneous paroxysmal unilateral facial pain, and carried a diagnosis of TN. Magnetic resonance imaging showed unilateral neurovascular compression, consistent with pain in areas innervated by the second branch of the trigeminal nerve. Genetic analysis as part of a phase 2 clinical study in patients with TN conducted by Convergence Pharmaceuticals Ltd revealed a previously undescribed de novo missense mutation in Na
1.6 (c.A406G; p.Met136Val). Whole-cell voltage-clamp recordings show that the Met136Val mutation significantly increases peak current density (1.5-fold) and resurgent current (1.6-fold) without altering gating properties. Current-clamp studies in trigeminal ganglion (TRG) neurons showed that Met136Val increased the fraction of high-firing neurons, lowered the current threshold and increased the frequency of evoked action potentials in response to graded stimuli. Our results demonstrate a novel Na
1.6 mutation in TN, and show that this mutation potentiates transient and resurgent sodium currents and leads to increased excitability in TRG neurons. We suggest that this gain-of-function Na
1.6 mutation may exacerbate the pathophysiology of vascular compression and contribute to TN.
COVID‐19 is characterized by dysregulated immune responses, metabolic dysfunction and adverse effects on the function of multiple organs. To understand host responses to COVID‐19 pathophysiology, we ...combined transcriptomics, proteomics, and metabolomics to identify molecular markers in peripheral blood and plasma samples of 66 COVID‐19‐infected patients experiencing a range of disease severities and 17 healthy controls. A large number of expressed genes, proteins, metabolites, and extracellular RNAs (exRNAs) exhibit strong associations with various clinical parameters. Multiple sets of tissue‐specific proteins and exRNAs varied significantly in both mild and severe patients suggesting a potential impact on tissue function. Chronic activation of neutrophils, IFN‐I signaling, and a high level of inflammatory cytokines were observed in patients with severe disease progression. In contrast, COVID‐19‐infected patients experiencing milder disease symptoms showed robust T‐cell responses. Finally, we identified genes, proteins, and exRNAs as potential biomarkers that might assist in predicting the prognosis of SARS‐CoV‐2 infection. These data refine our understanding of the pathophysiology and clinical progress of COVID‐19.
SYNOPSIS
Proteomics, metabolomics and RNAseq data map immune responses in COVID‐19 patients with different disease severity, revealing molecular makers associated with disease progression and alterations of tissue‐specific proteins.
A multi‐omics profiling of the host response to SARS‐CoV2 infection in 66 clinically diagnosed and laboratory confirmed COVID‐19 patients and 17 uninfected controls.
Significant correlations between multi‐omics data and key clinical parameters.
Alteration of tissue‐specific proteins and exRNAs.
Enhanced activation of immune responses is associated with COVID‐19 pathogenesis.
Biomarkers to predict COVID‐19 clinical outcomes pending clinical validation as prospective marker.
Proteomics, metabolomics and RNAseq data map immune responses in COVID‐19 patients with different disease severity, revealing molecular makers associated with disease progression and alterations of tissue‐specific proteins.
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