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The autonomic regulation of the pulmonary vasculature has been under‐appreciated despite the presence of sympathetic and parasympathetic neural innervation and adrenergic and cholinergic receptors on pulmonary vessels. Recent clinical trials targeting this innervation have demonstrated promising effects in pulmonary hypertension, and in this context of reignited interest, we review autonomic pulmonary vascular regulation, its integration with other pulmonary vascular regulatory mechanisms, systemic homeostatic reflexes and their clinical relevance in pulmonary hypertension. The sympathetic and parasympathetic nervous systems can affect pulmonary vascular tone and pulmonary vascular stiffness. Local afferents in the pulmonary vasculature are activated by elevations in pressure and distension and lead to distinct pulmonary baroreflex responses, including pulmonary vasoconstriction, increased sympathetic outflow, systemic vasoconstriction and increased respiratory drive. Autonomic pulmonary vascular control interacts with, and potentially makes a functional contribution to, systemic homeostatic reflexes, such as the arterial baroreflex. New experimental therapeutic applications, including pulmonary artery denervation, pharmacological cholinergic potentiation, vagal nerve stimulation and carotid baroreflex stimulation, have shown some promise in the treatment of pulmonary hypertension. What is the topic of this review?This review examines our understanding of the autonomic control of pulmonary circulation, with an emphasis on its clinical relevance and potential therapeutic targeting in pulmonary hypertension.What advances does it highlight?The sympathetic and parasympathetic nervous systems both regulate pulmonary vascular tone and stiffness, in integration with systemic autonomic homeostasis. Pulmonary vascular afferents responsive to pulmonary arterial pressure produce distinct pulmonary baroreflex responses. Dysfunction in autonomic control both to and from the pulmonary vasculature might contribute to pulmonary hypertension, and new approaches targeting this have demonstrated early success. [ABSTRACT FROM AUTHOR]

The past two decades have witnessed a wide range of studies investigating genetic variants of voltage‐gated sodium (NaV) channels, which are involved in a broad spectrum of diseases, including several types of epilepsy. We have reviewed here phenotypes and pathological mechanisms of genetic epilepsies caused by variants in NaV α and β subunits, as well as of some relevant interacting proteins (FGF12/FHF1, PRRT2, and Ankyrin‐G). Notably, variants of all these genes can induce either gain‐ or loss‐of‐function of NaV leading to either neuronal hyperexcitability or hypoexcitability. We present the results of functional studies obtained with different experimental models, highlighting that they should be interpreted considering the features of the experimental system used. These systems are models, but they have allowed us to better understand pathophysiological issues, ameliorate diagnostics, orientate genetic counseling, and select/develop therapies within a precision medicine framework. These studies have also allowed us to gain insights into the physiological roles of different NaV channels and of the cells that express them. Overall, our review shows the progress that has been made, but also the need for further studies on aspects that have not yet been clarified. Finally, we conclude by highlighting some significant themes of general interest that can be gleaned from the results of the work of the last two decades. [ABSTRACT FROM AUTHOR]

Background: Patients with nonalcoholic fatty liver disease (NAFLD) are reported to have a higher risk of osteoporosis/fractures; however, the causal relationship remains unclear. Methods: Publicly available genome‐wide association studies (GWASs) were used for Mendelian randomization (MR) analysis. GWASs of NAFLD and fractures were obtained from the FinnGen Consortium. GWASs of bone mineral density (BMD) were derived from a meta‐analysis. GWASs of obesity, diabetes, liver function, and serum lipid‐related metrics were used to clarify whether the accompanying NAFLD symptoms contributed to fractures. Moreover, two additional GWASs of NAFLD were applied. Results: A causal association was not observed between NAFLD and BMD using GWASs from the FinnGen Consortium. However, a causal relationship between NAFLD and femoral neck‐BMD (FN‐BMD), a suggestive relationship between fibrosis and FN‐BMD, and between NAFLD and osteoporosis were identified in replication GWASs. Genetically proxied body mass index (BMI), high‐density lipoprotein (HDL), and hip circumference increased the likelihood of lower limb fractures. The waist‐to‐hip ratio decreased, whereas glycated hemoglobin (HbA1C) and homeostasis model assessment of β‐cell function (HOMA‐B) increased the risk of forearm fractures. Low‐density lipoprotein (LDL) reduced, whereas HbA1C increased the incidence of femoral fractures. Alkaline phosphatase (ALP) raised the risk of foot fractures. However, after a multivariate MR analysis (adjusted for BMI), all the relationships became insignificant. Conclusions: NAFLD caused reduced BMD, and genetically predicted HDL, LDL, HbA1C, HOMA‐B, ALP, hip circumference, and waist‐to‐hip ratio causally increased the risk of fractures. BMI may mediate causal relationships. Larger GWASs are required to verify this finding. [ABSTRACT FROM AUTHOR]

Heart failure with preserved ejection fraction (HFpEF) accounts for over 50% of all heart failure cases nationwide and continues to rise in its prevalence. The complex, multi‐organ involvement of the HFpEF clinical syndrome requires clinicians and investigators to adopt an integrative approach that considers the contribution of both cardiac and non‐cardiac function to HFpEF pathophysiology. Thus, this symposium review outlines the key points from presentations covering the contributions of disease‐related changes in cardiac function, arterial stiffness, peripheral vascular function, and oxygen delivery and utilization to exercise tolerance in patients with HFpEF. While many aspects of HFpEF pathophysiology remain poorly understood, there is accumulating evidence for a decline in vascular health in this patient group that may be remediable through pharmacological and lifestyle interventions and could improve outcomes and clinical status in this ever‐growing patient population. What is the topic of this review?This symposium review provides an integrative view of how disease‐related changes in cardiac, vascular and skeletal muscle function contribute to exercise intolerance in patients with heart failure with preserved ejection fraction (HFpEF).What advances does it highlight?Emerging evidence continues to highlight the importance of considering both cardiac and non‐cardiac abnormalities in patients with HFpEF, with accumulating evidence for 'plasticity' in vascular function that emphasizes the need for a greater focus on strategies targeting the peripheral circulation as a means to improve exercise intolerance. [ABSTRACT FROM AUTHOR]

Aims: We aimed to clarify the extent to which cardiac and peripheral impairments to oxygen delivery and utilization contribute to exercise intolerance and risk for adverse events, and how this relates to diversity and multiplicity in pathophysiologic traits. Methods and results: Individuals with heart failure with preserved ejection fraction (HFpEF) and non‐cardiac dyspnoea (controls) underwent invasive cardiopulmonary exercise testing and clinical follow‐up. Haemodynamics and oxygen transport responses were compared. HFpEF patients were then categorized a priori into previously‐proposed, non‐exclusive descriptive clinical trait phenogroups, including cardiometabolic, pulmonary vascular disease, left atrial myopathy, and vascular stiffening phenogroups based on clinical and haemodynamic profiles to contrast pathophysiology and clinical risk. Overall, patients with HFpEF (n = 643) had impaired cardiac output reserve with exercise (2.3 vs. 2.8 L/min, p = 0.025) and greater reliance on peripheral oxygen extraction augmentation (4.5 vs. 3.8 ml/dl, p < 0.001) compared to dyspnoeic controls (n = 219). Most (94%) patients with HFpEF met criteria for at least one clinical phenogroup, and 67% fulfilled criteria for multiple overlapping phenogroups. There was greater impairment in peripheral limitations in the cardiometabolic group and greater cardiac output limitations and higher pulmonary vascular resistance during exertion in the other phenogroups. Increasing trait multiplicity within a given patient was associated with worse exercise haemodynamics, poorer exercise capacity, lower cardiac output reserve, and greater risk for heart failure hospitalization or death (hazard ratio 1.74, 95% confidence interval 1.08–2.79 for 0–1 vs. ≥2 phenogroup traits present). Conclusions: Though cardiac output response to exercise is limited in patients with HFpEF compared to those with non‐cardiac dyspnoea, the relative contributions of cardiac and peripheral limitations vary with differing numbers and types of clinical phenotypic traits present. Patients fulfilling criteria for greater multiplicity and diversity of HFpEF phenogroup traits have poorer exercise capacity, worsening haemodynamic perturbations, and greater risk for adverse outcome. [ABSTRACT FROM AUTHOR]

Despite remarkable improvements in the management of heart failure (HF), HF remains one of the most rapidly growing cardiovascular condition resulting in a substantial burden on healthcare systems worldwide. In clinical practice, however, a relevant proportion of patients are treated with suboptimal combinations and doses lower than those recommended in the current guidelines. Against this background, it remains important to identify new targets and investigate additional therapeutic options to alleviate symptoms and potentially improve prognosis in HF. Therefore, non‐pharmacological interventions targeting autonomic imbalance in HF have been evaluated. This paper aims to review the physiology, available clinical data, and potential therapeutic role of device‐based neuromodulation in HF. [ABSTRACT FROM AUTHOR]

Preprocessing fMRI data requires striking a fine balance between conserving signals of interest and removing noise. Typical steps of preprocessing include motion correction, slice timing correction, spatial smoothing, and high‐pass filtering. However, these standard steps do not remove many sources of noise. Thus, noise‐reduction techniques, for example, CompCor, FIX, and ICA‐AROMA have been developed to further improve the ability to draw meaningful conclusions from the data. The ability of these techniques to minimize noise while conserving signals of interest has been tested almost exclusively in resting‐state fMRI and, only rarely, in task‐related fMRI. Application of noise‐reduction techniques to task‐related fMRI is particularly important given that such procedures have been shown to reduce false positive rates. Little remains known about the impact of these techniques on the retention of signal in tasks that may be associated with systemic physiological changes. In this paper, we compared two ICA‐based, that is FIX and ICA‐AROMA, two CompCor‐based noise‐reduction techniques, that is aCompCor, and tCompCor, and standard preprocessing using a large (n = 101) fMRI dataset including noxious heat and non‐noxious auditory stimulation. Results show that preprocessing using FIX performs optimally for data obtained using noxious heat, conserving more signals than CompCor‐based techniques and ICA‐AROMA, while removing only slightly less noise. Similarly, for data obtained during non‐noxious auditory stimulation, FIX noise‐reduction technique before analysis with a covariate of interest outperforms the other techniques. These results indicate that FIX might be the most appropriate technique to achieve the balance between conserving signals of interest and removing noise during task‐related fMRI. [ABSTRACT FROM AUTHOR]

Orthopedic patients need to perform limb immobilization for several days to several weeks due to fracture or other special circumstances. When the function of a certain part or the whole body is restricted, the activity of osteoclasts will be enhanced and its life activity will surpass that of osteoblasts, so local or even whole body bone loss will occur. Acute bone loss usually occurs within a few weeks after the immobilization of limbs. At this stage, the patient's bone mass will decrease sharply, and the patient is prone to osteoporotic refracture. After that, the bone mass will gradually recover, but the speed of bone formation and bone absorption is difficult to reach a balanced state, and the bone mass of patients will continue to decline after it has recovered to a certain degree. After acute progressive bone loss, a large number of bones were lost and the strength of bones decreased. It is often difficult to recover to the level before fracture for a long time, which undoubtedly increases the risk of osteoporosis and related refractures. According to this common phenomenon of bone loss, clinical treatment varies greatly. After a series of research and practice, clinicians summed up some rules and put forward some feasible suggestions, thus strengthening clinicians' understanding of the treatment of acute bone loss, effectively improving the treatment effect of acute bone loss, having far-reaching significance for preventing and treating osteoporosis, reducing the risk of fracture, and improving the long-term prognosis of patients. [ABSTRACT FROM AUTHOR]

We have devised the unified redox scale EabsH2O, which is valid for all solvents. The necessary single ion Gibbs transfer energy between two different solvents, which only can be determined with extra‐thermodynamic assumptions so far, must clearly satisfy two essential conditions: First, the sum of the independent cation and anion values must give the Gibbs transfer energy of the salt they form. The latter is an observable and measurable without extra‐thermodynamic assumptions. Second, the values must be consistent for different solvent combinations. With this work, potentiometric measurements on silver ions and on chloride ions show that both conditions are fulfilled using a salt bridge filled with the ionic liquid [N2225][NTf2]: if compared to the values resulting from known pKL values, the silver and chloride single ion magnitudes combine within a uncertainty of 1.5 kJ mol−1 to the directly measurable transfer magnitudes of the salt AgCl from water to the solvents acetonitrile, propylene carbonate, dimethylformamide, ethanol, and methanol. The resulting values are used to further develop the consistent unified redox potential scale EabsH2O that now allows to assess and compare redox potentials in and over six different solvents. We elaborate on its implications. [ABSTRACT FROM AUTHOR]

Although the piriform cortex (PC) has been previously implicated as a critical node for seizure generation and propagation, the underlying neural mechanism has remained unclear. Here, we found increased excitability in PC neurons during amygdala kindling acquisition. Optogenetic or chemogenetic activation of PC pyramidal neurons promoted kindling progression, whereas inhibition of these neurons retarded seizure activities induced by electrical kindling in the amygdala. Furthermore, chemogenetic inhibition of PC pyramidal neurons alleviated the severity of kainic acid‐induced acute seizures. These results demonstrate that PC pyramidal neurons bidirectionally modulate seizures in temporal lobe epilepsy, providing evidence for the efficacy of PC pyramidal neurons as a potential therapeutic target for epileptogenesis. Key points: While the piriform cortex (PC) is an important olfactory centre critically involved in olfactory processing and plays a crucial role in epilepsy due to its close connection with the limbic system, how the PC regulates epileptogenesis is largely unknown.In this study, we evaluated the neuronal activity and the role of pyramidal neurons in the PC in the mouse amygdala kindling model of epilepsy.PC pyramidal neurons are hyperexcited during epileptogenesis.Optogenetic and chemogenetic activation of PC pyramidal neurons significantly promoted seizures in the amygdala kindling model, whereas selective inhibition of these neurons produced an anti‐epileptic effect for both electrical kindling and kainic acid‐induced acute seizures.The results of the present study indicate that PC pyramidal neurons bidirectionally modulate seizure activity. [ABSTRACT FROM AUTHOR]

Aims: Comorbidities play a significant role towards the pathophysiology of heart failure with preserved ejection fraction (HFpEF), characterized by abnormal macrovascular function and altered ventricular–vascular coupling. However, our understanding of the role of comorbidities and arterial stiffness in HFpEF remains incomplete. We hypothesized that HFpEF is preceded by a cumulative rise in arterial stiffness as cardiovascular comorbidities accumulate, beyond that associated with ageing. Methods and results: Arterial stiffness was assessed using pulse wave velocity (PWV) in five groups: Group A, healthy volunteers (n = 21); Group B, patients with hypertension (n = 21); Group C, hypertension and diabetes mellitus (n = 20); Group D, HFpEF (n = 21); and Group E, HF with reduced ejection fraction (HFrEF) (n = 11). All patients were aged 70 and above. Mean PWV increased from Groups A to D (PWV 10.2, 12.2, 13.0, and 13.7 m/s, respectively) as vascular comorbidities accumulated independent of age, renal function, haemoglobin, obesity (body mass index), smoking status, and hypercholesterolaemia. HFpEF exhibited the highest PWV and HFrEF displayed near‐normal levels (13.7 vs. 10 m/s, P = 0.003). PWV was inversely related to peak oxygen consumption (r = −0.304, P = 0.03) and positively correlated with left ventricular filling pressures (E/e′) on echocardiography (r = −0.307, P = 0.014). Conclusions: This study adds further support to the concept of HFpEF as a disease of the vasculature, underlined by an increasing arterial stiffness that is driven by vascular ageing and accumulating vascular comorbidities, for example, hypertension and diabetes. Reflecting a pulsatile arterial afterload associated with diastolic dysfunction and exercise capacity, PWV may provide a clinically relevant tool to identify at‐risk intermediate phenotypes (e.g. pre‐HFpEF) before overt HFpEF occurs. [ABSTRACT FROM AUTHOR]

Aims: Diagnosis of heart failure with preserved ejection fraction (HFpEF) remains challenging in patients presenting with chronic dyspnoea. We sought to determine the diagnostic value of reduced left atrial (LA) compliance during exercise to diagnose HFpEF. Methods and results: Ergometry exercise stress echocardiography was performed in 225 patients with HFpEF and 262 non‐heart failure controls (non‐cardiac dyspnoea [NCD]) in Protocol 1, where the diagnosis of HFpEF was defined by the HFA‐PEFF algorithm. In Protocol 2, the diagnosis of HFpEF was ascertained by exercise right heart catheterization in 67 participants (49 HFpEF and 18 NCD). Speckle‐tracking echocardiography was performed at rest and during exercise to determine LA compliance (ratio of LA reservoir strain to E/e'). As compared with NCD, patients with HFpEF demonstrated decreased LA reservoir strain and compliance at rest, and these differences further increased during exercise in Protocol 1. Exercise LA compliance discriminated HFpEF from NCD (area under the curve 0.87, p < 0.0001), with a superior diagnostic ability to exercise E/e' ratio (DeLong p = 0.005). Exercise LA compliance demonstrated incremental diagnostic value over clinical factors (age, systemic hypertension, and atrial fibrillation) and resting LA compliance (χ2 212.4 vs. 166.2, p < 0.0001). These findings were confirmed in Protocol 2. Conclusion: Left atrial compliance during exercise demonstrated superior diagnostic ability to exercise E/e' ratio, with incremental diagnostic value over the resting LA compliance. Exercise LA compliance may enhance the diagnosis of HFpEF among patients with dyspnoea. [ABSTRACT FROM AUTHOR]

Aims: Cardiac and extracardiac abnormalities play important roles in heart failure with preserved ejection fraction (HFpEF). Biventricular cardiac power output (BCPO) quantifies the total rate of hydraulic work performed by both ventricles, suggesting that it may help to identify patients with HFpEF and more severe cardiac impairments to better individualize treatment. Methods and results: Patients with HFpEF (n = 398) underwent comprehensive echocardiography and invasive cardiopulmonary exercise testing. Patients were categorized as low BCPO reserve (n = 199, < median of 1.57 W) or preserved BCPO reserve (n = 199). As compared to those with preserved BCPO reserve, those with low reserve were older and leaner, with more atrial fibrillation, higher N‐terminal pro‐B‐type natriuretic peptide levels, worse renal function, more impaired left ventricular (LV) global longitudinal strain, worse LV diastolic function and right ventricular longitudinal function. Cardiac filling pressures and pulmonary artery pressures at rest were higher in low BCPO reserve, but central pressures were similar during exercise to those with preserved BCPO reserve. Exertional systemic and pulmonary vascular resistances were higher and exercise capacity was more impaired in those with low BCPO reserve. Reduced BCPO reserve was associated with increased risk for the composite endpoint of heart failure hospitalization or death over 2.9 (interquartile range 0.9–4.5) years of follow‐up (hazard ratio 2.77, 95% confidence interval 1.73–4.42, p < 0.0001). Conclusions: Inability to enhance BCPO during exercise is associated with more advanced HFpEF, increased systemic and pulmonary vascular resistance, reduced exercise capacity and increased adverse events in patients with HFpEF. Novel therapies that enhance biventricular reserve merit further investigation for patients with this phenotype. [ABSTRACT FROM AUTHOR]

Heart failure with preserved ejection fraction (HFpEF) represents a highly heterogeneous clinical syndrome affected in its development and progression by many comorbidities. The left ventricular diastolic dysfunction may be a manifestation of various combinations of cardiovascular, metabolic, pulmonary, renal, and geriatric conditions. Thus, in addition to treatment with sodium–glucose cotransporter 2 inhibitors in all patients, the most effective method of improving clinical outcomes may be therapy tailored to each patient's clinical profile. To better outline a phenotype‐based approach for the treatment of HFpEF, in this joint position paper, the Heart Failure Association of the European Society of Cardiology, the European Heart Rhythm Association and the European Hypertension Society, have developed an algorithm to identify the most common HFpEF phenotypes and identify the evidence‐based treatment strategy for each, while taking into account the complexities of multiple comorbidities and polypharmacy. [ABSTRACT FROM AUTHOR]

Over the last two decades, the changing paradigm of heart failure with preserved ejection fraction (HFpEF) has transformed our understanding not only of the pathophysiology of this clinical entity but also the diagnostic and therapeutic approaches aimed at treating this complex patient population. No longer HFpEF should be seen as simply left ventricular diastolic dysfunction but as a group of that in addition of having small and thick left ventricles with abnormal diastolic filling patterns as their main pathophysiologic abnormality; they also have whole host of different abnormalities. In fact, this heterogeneous clinical entity embodies numerous mechanisms and is linked to multiorgan dysfunction, with hypertension and obesity playing a major role. Although we have gained an enormous amount of understanding not only on the causes but also the downstream effects of HFpEF, there is still much to be learned before we can fully comprehend this complex clinical entity. It is the main intention of this review to synthesize the most recent attributes, mechanism, diagnostic tools, and most useful therapeutic alternatives to be considered when evaluating patients either complaining of dyspnea on exertion as well as exercise intolerance or those recently admitted with HF symptoms but with normal LVEF in the absence of any other valvular abnormalities [ABSTRACT FROM AUTHOR]

Aims: Pulmonary hypertension (PH) and pulmonary vascular remodelling are common in patients with heart failure with preserved ejection fraction (HFpEF). Many patients with HFpEF demonstrate an abnormal pulmonary haemodynamic response to exercise that is not identifiable at rest. This can be estimated non‐invasively by the mean pulmonary artery pressure–cardiac output relationship (mPAP/CO slope). We sought to characterize the pathophysiology of disproportionate exercise‐induced PH in relation to CO (DEi‐PH) and its prognostic impact in patients with HFpEF. Methods and results: A total of 345 patients (166 HFpEF and 179 controls) underwent ergometry exercise stress echocardiography with simultaneous expired gas analysis. DEi‐PH was defined as the mPAP/CO slope >5.2 mmHg/L/min (median value). At rest, there were no differences in right ventricular (RV) function and severity of PH between HFpEF patients with and without DEi‐PH. Compared with controls (n = 179) and HFpEF without DEi‐PH (n = 83), HFpEF with DEi‐PH (n = 83) demonstrated worse exercise capacity (lower peak oxygen consumption), depressed RV systolic function, impaired RV–pulmonary artery coupling, limitation in CO augmentation, more right‐sided congestion, and worse ventilatory efficiency (higher minute ventilation vs. carbon dioxide volume) during peak exercise. Kaplan–Meier analyses showed that HFpEF patients with DEi‐PH had higher rates of composite outcomes of all‐cause mortality or heart failure events than those without (log‐rank p = 0.0002). Conclusion: Patients with HFpEF and DEi‐PH demonstrated distinct pathophysiologic features that become apparent only during exercise. These data suggest that DEi‐PH is a pathophysiologic phenotype of HFpEF and reinforce the importance of exercise stress echocardiography for detailed characterization of HFpEF. [ABSTRACT FROM AUTHOR]

The piriform cortex (PC) is located at the junction of the temporal and frontal lobes. It is involved physiologically in olfaction as well as memory and plays an important role in epilepsy. Its study at scale is held back by the absence of automatic segmentation methods on MRI. We devised a manual segmentation protocol for PC volumes, integrated those manually derived images into the Hammers Atlas Database (n = 30) and used an extensively validated method (multi‐atlas propagation with enhanced registration, MAPER) for automatic PC segmentation. We applied automated PC volumetry to patients with unilateral temporal lobe epilepsy with hippocampal sclerosis (TLE; n = 174 including n = 58 controls) and to the Alzheimer's Disease Neuroimaging Initiative cohort (ADNI; n = 151, of whom with mild cognitive impairment (MCI), n = 71; Alzheimer's disease (AD), n = 33; controls, n = 47). In controls, mean PC volume was 485 mm3 on the right and 461 mm3 on the left. Automatic and manual segmentations overlapped with a Jaccard coefficient (intersection/union) of ~0.5 and a mean absolute volume difference of ~22 mm3 in healthy controls, ~0.40/ ~28 mm3 in patients with TLE, and ~ 0.34/~29 mm3 in patients with AD. In patients with TLE, PC atrophy lateralised to the side of hippocampal sclerosis (p <.001). In patients with MCI and AD, PC volumes were lower than those of controls bilaterally (p <.001). Overall, we have validated automatic PC volumetry in healthy controls and two types of pathology. The novel finding of early atrophy of PC at the stage of MCI possibly adds a novel biomarker. PC volumetry can now be applied at scale. [ABSTRACT FROM AUTHOR]

Aims: Ancillary analyses from clinical trials have suggested reduced efficacy for neurohormonal antagonists among patients with heart failure and preserved ejection fraction (HFpEF) and higher ranges of ejection fraction (EF). Methods and results: A total of 621 patients with HFpEF were grouped into those with low‐normal left ventricular EF (LVEF) (HFpEF<65%, n = 319, 50% ≤ LVEF <65%) or HFpEF≥65% (n = 302, LVEF ≥65%), and compared with 149 age‐matched controls undergoing comprehensive echocardiography and invasive cardiopulmonary exercise testing. A sensitivity analysis was performed in a second non‐invasive community‐based cohort of patients with HFpEF (n = 244) and healthy controls without cardiovascular disease (n = 617). Patients with HFpEF≥65% had smaller left ventricular (LV) end‐diastolic volume than HFpEF<65%, but LV systolic function assessed by preload recruitable stroke work and stroke work/end‐diastolic volume was similarly impaired. Patients with HFpEF≥65% displayed an end‐diastolic pressure–volume relationship (EDPVR) that was shifted leftward, with increased LV diastolic stiffness constant β, in both invasive and community‐based cohorts. Cardiac filling pressures and pulmonary artery pressures at rest and during exercise were similarly abnormal in all EF subgroups. While patients HFpEF≥57% displayed leftward shifted EDPVR, those with HFpEF<57% had a rightward shifted EDPVR more typical of heart failure with reduced EF. Conclusion: Most pathophysiologic differences in patients with HFpEF and higher EF are related to smaller heart size, increased LV diastolic stiffness, and leftward shift in the EDPVR. These findings may help to explain the absence of efficacy for neurohormonal antagonists in this group and raise a new hypothesis, that interventions to stimulate eccentric LV remodelling and enhance diastolic capacitance may be beneficial for patients with HFpEF and EF in the higher range. [ABSTRACT FROM AUTHOR]

Aims: Limited evidence is available regarding the role of hypertensive response to exercise (HRE) in heart failure (HF). We evaluated the systolic blood pressure (SBP) to workload slope during exercise across the HF spectrum, investigating haemodynamic and prognostic correlates of HRE. Methods and results: We prospectively enrolled 369 patients with HF Stage C (143 had preserved [HFpEF], and 226 reduced [HFrEF] ejection fraction), 201 subjects at risk of developing HF (HF Stages A–B), and 58 healthy controls. We performed a combined cardiopulmonary exercise stress echocardiography testing. We defined HRE as the highest sex‐specific SBP/workload slope tertile in each HF stage. Median SBP/workload slope was 0.53 mmHg/W (interquartile range 0.36–0.72); the slope was 39% steeper in women than men (p < 0.0001). After adjusting for age and sex, SBP/workload slope in HFrEF (0.47, 0.30–0.63) was similar to controls (0.43, 0.35–0.57) but significantly lower than Stages A–B (0.61, 0.47–0.75) and HFpEF (0.63, 0.42–0.86). Patients with HRE showed significantly lower peak oxygen consumption and peripheral oxygen extraction. After a median follow‐up of 16 months, HRE was independently associated with adverse outcomes (all‐cause mortality and hospitalization for cardiovascular reasons: hazard ratio 2.05, 95% confidence interval 1.81–5.18), while rest and peak SBP were not. Kaplan–Meier analysis confirmed a worse survival probability in Stages A–B (p = 0.005) and HFpEF (p < 0.001), but not HFrEF. Conclusion: A steeper SBP/workload slope is associated with impaired functional capacity across the HF spectrum and could be a more sensitive predictor of adverse events than absolute SBP values, mainly in patients in Stages A–B and HFpEF. [ABSTRACT FROM AUTHOR]

Aims: Chronic heart failure (HF) is a common disease and one of the leading causes of death worldwide. Heart failure with preserved ejection fraction (HFpEF) and with reduced ejection fraction (HFrEF) are different diseases with distinct as well as comparable pathophysiologies and diverse responses to therapeutic agents. We aimed to identify possible pathobiochemical signalling pathways and biomarkers in HFpEF and HFrEF by using a broad proteomic approach. Methods and results: A total of 180 biomarkers in the plasma of a representative subgroup (71 years old) of HFpEF (70% female) with a left ventricular ejection fraction (LVEF) ≥ 50% and HFrEF (18% female) with an LVEF ≤ 40% patients (n = 127) from the Prevalence and Clinical Course of Diastolic Dysfunction and Diastolic Heart Failure (DIAST‐CHF) trial were examined and compared with a healthy control group (n = 40; 48% female). We were able to identify 35 proteins that were expressed significantly different in both HF groups compared with the control group. We determine 29 unique proteins expressed in HFpEF and 33 unique proteins in HFrEF. Significantly up‐regulated trefoil factor 3 (TFF3) and down‐regulated contactin‐1 could be identified as previously unknown biomarkers for HF. However, TFF3 is also a predictive factor for the occurrence of a cardiovascular event in HFpEF patients. In HFpEF, serine protease 27 was found at reduced levels for the first time, which could offer a new therapeutic target. Additionally, network analyses showed a special role of platelet‐derived growth factor subunit A, Dickkopf‐related protein 1, and tumour necrosis factor receptor superfamily member 6 in HFpEF patients, whereas perlecan and junctional adhesion molecule A stood out in the HFrEF group. Overall, signalling pathways of metabolic processes, cellular stress, and iron metabolism seemed to be important for HFrEF, whereas for HFpEF, oxygen stress, haemostasis, cell renewal, cell migration, and cell proliferation are in the foreground. Conclusions: The identified proteins and signalling pathways offer new therapeutic and diagnostic approaches for patients with chronic HF. [ABSTRACT FROM AUTHOR]

Half of these patients had a diagnosis of acute HF and presented higher levels of interleukin-6 compared to patients with other causes of dyspnoea. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: developed by the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Baroreflex activation therapy with the Barostim device in patients with heart failure with reduced ejection fraction: a patient level meta-analysis of randomized controlled trials. Sympathetic activity Autonomic nervous system is a main target on novel interventions.[[1], [3]] Badrov I et al i .[5] investigated determinants of augmented muscle sympathetic nerve activity (MSNA) in 177 heart failure (HF) patients and 658 healthy volunteers. [Extracted from the article]

In the last years, major progress occurred in heart failure (HF) management. Quadruple therapy is now mandatory for all the patients with HF with reduced ejection fraction. Whilst verciguat is becoming available across several countries, omecamtiv mecarbil is waiting to be released for clinical use. Concurrent use of potassium‐lowering agents may counteract hyperkalaemia and facilitate renin–angiotensin–aldosterone system inhibitor implementations. The results of the EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Preserved Ejection Fraction (EMPEROR‐Preserved) trial were confirmed by the Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction (DELIVER) trial, and we now have, for the first time, evidence for treatment of also patients with HF with preserved ejection fraction. In a pre‐specified meta‐analysis of major randomized controlled trials, sodium–glucose co‐transporter‐2 inhibitors reduced all‐cause mortality, cardiovascular (CV) mortality, and HF hospitalization in the patients with HF regardless of left ventricular ejection fraction. Other steps forward have occurred in the treatment of decompensated HF. Acetazolamide in Acute Decompensated Heart Failure with Volume Overload (ADVOR) trial showed that the addition of intravenous acetazolamide to loop diuretics leads to greater decongestion vs. placebo. The addition of hydrochlorothiazide to loop diuretics was evaluated in the CLOROTIC trial. Torasemide did not change outcomes, compared with furosemide, in TRANSFORM‐HF. Ferric derisomaltose had an effect on the primary outcome of CV mortality or HF rehospitalizations in IRONMAN (rate ratio 0.82; 95% confidence interval 0.66–1.02; P = 0.070). Further options for the treatment of HF, including device therapies, cardiac contractility modulation, and percutaneous treatment of valvulopathies, are summarized in this article. [ABSTRACT FROM AUTHOR]

Aims: Heart failure with preserved ejection fraction (HFpEF) is one of the most rapidly growing cardiovascular health burden worldwide, but there is still a lack of understanding about the HFpEF pathophysiology. The nitric oxide (NO) signalling pathway has been identified as a potential key element. The aim of our study was to investigate markers of NO metabolism [l‐arginine (l‐Arg), homoarginine (hArg), and asymmetric and symmetric dimethylarginine (ADMA and SDMA)], additional biomarkers [N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP), endothelin‐1 (ET‐1), mid‐regional pro‐adrenomedullin (MR‐proADM), copeptin, and high‐sensitivity C‐reactive protein (hsCRP)], and the endothelial function in an integrated approach focusing on associations with clinical characteristics in patients with HFpEF. Methods and results: Seventy‐three patients, prospectively enrolled in the 'German HFpEF Registry', were analysed. Inclusion criteria were left ventricular ejection fraction (LVEF) ≥ 50%; New York Heart Association functional class ≥ II; elevated levels of NT‐proBNP > 125 pg/mL; and at least one additional criterion for structural heart disease or diastolic dysfunction. All patients underwent transthoracic echocardiography, cardiopulmonary exercise testing, and pulse amplitude tonometry (EndoPAT™). Patients were categorized in two groups based on their retrospectively calculated HFA‐PEFF score. Serum concentrations of l‐Arg, hArg, ADMA, SDMA, NT‐proBNP, ET‐1, MR‐proADM, copeptin, and hsCRP were determined. Patients had a median age of 74 years, 47% were female, and median LVEF was 57%. Fifty‐two patients (71%) had an HFA‐PEFF score ≥ 5 (definitive HFpEF), and 21 patients (29%) a score of 3 to 4 (risk for HFpEF). Overall biomarker concentrations were 126 ± 32 μmol/L for l‐Arg, 1.67 ± 0.55 μmol/L for hArg, 0.74 (0.60;0.85) μmol/L for SDMA, and 0.61 ± 0.10 μmol/L for ADMA. The median reactive hyperaemia index (RHI) was 1.55 (1.38;1.87). SDMA correlated with NT‐proBNP (r = 0.291; P = 0.013), ET‐1 (r = 0.233; P = 0.047), and copeptin (r = 0.381; P = 0.001). ADMA correlated with ET‐1 (r = 0.250; P = 0.033) and hsCRP (r = 0.303; P = 0.009). SDMA was associated with the left atrial volume index (β = 0.332; P = 0.004), also after adjustment for age, sex, and comorbidities. Biomarkers were non‐associated with the RHI. A principal component analysis revealed two contrary clusters of biomarkers. Conclusions: Our findings suggest an impaired NO metabolism as one possible key pathogenic determinant in at least a subgroup of patients with HFpEF. We argue for further evaluation of NO‐based therapies. Upcoming studies should clarify whether subgroups of HFpEF patients can take more benefit from therapies that are targeting NO metabolism and pathway. [ABSTRACT FROM AUTHOR]

Aims: Evidence on the association between ambient temperature and the onset of acute heart failure (AHF) is scarce and mixed. We sought to investigate the incidence of AHF admissions based on ambient temperature change, with particular interest in detecting the difference between AHF with preserved (HFpEF), mildly reduced (HFmrEF), and reduced ejection fraction (HFrEF). Methods and results: Individualized AHF admission data from January 2015 to December 2016 were obtained from a multicentre registry (Tokyo CCU Network Database). The primary event was the daily number of admissions. A linear regression model, using the lowest ambient temperature as the explanatory variable, was selected for the best‐estimate model. We also applied the cubic spline model using five knots according to the percentiles of the distribution of the lowest ambient temperature. We divided the entire population into HFpEF + HFmrEF and HFrEF for comparison. In addition, the in‐hospital treatment and mortality rates were obtained according to the interquartile ranges (IQRs) of the lowest ambient temperature (IQR1 <5.5°C; IQR25.5–13.3°C; IQR3 13.3–19.7°C; and IQR4 >19.7°C). The number of admissions for HFpEF, HFmrEF and HFrEF were 2736 (36%), 1539 (20%), and 3354 (44%), respectively. The lowest ambient temperature on the admission day was inversely correlated with the admission frequency for both HFpEF + HFmrEF and HFrEF patients, with a stronger correlation in patients with HFpEF + HFmrEF (R2 = 0.25 vs. 0.05, P < 0.001). In the sensitivity analysis, the decrease in the ambient temperature was associated with the greatest incremental increases in HFpEF, followed by HFmrEF and HFrEF patients (3.5% vs. 2.8% vs. 1.5% per −1°C, P < 0.001), with marked increase in admissions of hypertensive patients (systolic blood pressure >140 mmHg vs. 140–100 mmHg vs. <100 mmHg, 3.0% vs. 2.0% vs. 0.8% per −1°C, P for interaction <0.001). A mediator analysis indicated the presence of the mediator effect of systolic blood pressure. The in‐hospital mortality rate (7.5%) did not significantly change according to ambient temperature (P = 0.62). Conclusions: Lower ambient temperature was associated with higher frequency of AHF admissions, and the effect was more pronounced in HFpEF and HFmrEF patients than in those with HFrEF. [ABSTRACT FROM AUTHOR]

Aims: Exercise right heart catheterization (RHC) is considered the gold‐standard test to diagnose heart failure with preserved ejection fraction (HFpEF). However, exercise RHC is an insufficiently standardized technique, and current haemodynamic thresholds to define HFpEF are not universally accepted. We sought to describe the exercise haemodynamics profile of HFpEF cohorts reported in literature, as compared with control subjects. Methods and results: We performed a systematic literature review until December 2020. Studies reporting pulmonary artery wedge pressure (PAWP) at rest and peak exercise were extracted. Summary estimates of all haemodynamic variables were evaluated, stratified according to body position (supine/upright exercise). The PAWP/cardiac output (CO) slope during exercise was extrapolated. Twenty‐seven studies were identified, providing data for 2180 HFpEF patients and 682 controls. At peak exercise, patients with HFpEF achieved higher PAWP (30 [29–31] vs. 16 [15–17] mmHg, P < 0.001) and mean right atrial pressure (P < 0.001) than controls. These differences persisted after adjustment for age, sex, body mass index, and body position. However, peak PAWP values were highly heterogeneous among the cohorts (I2 = 93%), with a relative overlap with controls. PAWP/CO slope was steeper in HFpEF than in controls (3.75 [3.20–4.28] vs. 0.95 [0.30–1.59] mmHg/L/min, P value < 0.0001), even after adjustment for covariates (P = 0.007). Conclusions: Despite methodological heterogeneity, as well as heterogeneity of pooled haemodynamic estimates, the exercise haemodynamic profile of HFpEF patients is consistent across studies and characterized by a steep PAWP rise during exercise. More standardization of exercise haemodynamics may be advisable for a wider application in clinical practice. [ABSTRACT FROM AUTHOR]

Objective: This study examines the schemas that women employed during the COVID‐19 pandemic to make sense of their reproductive desires. Background: Existing research on reproduction during epidemics suggests that there are variable population responses to periods of long‐term social uncertainty. However, less is known about how individuals make sense of maintaining or adapting their reproductive desires during periods of social upheaval. Method: Twenty‐nine women aged 25–35 from a mid‐sized Midwestern county in the United States were recruited and interviewed about their experiences during the first 8 months of the COVID‐19 pandemic. They were asked about their daily lived experiences and their reproductive desires during in‐depth interviews. These interviews were transcribed and analyzed using thematic coding. Results: Participants used three normative schemas to describe their reproductive desires during the COVID‐19 pandemic. Heteronormative schemas were used by many participants to articulate their commitment to a heteronormative aged‐staged timeline of life events. Schemas of social support around being pregnant and giving birth were used by participants, primarily those who were currently or recently pregnant, to express grief and loss over the relational experience of having a new baby. Medicalized schemas were expressed by most participants to describe feelings of fear and risk at real or imagined encounters with medical institutions. Conclusion: The schemas that participants used to make sense of their reproductive desires demonstrate how sense‐making during a profound event that affects everyday realities allows participants to (re)articulate commitments to existing narratives that reinforce heterosexual, social, and medicalized hierarchies in reproduction. [ABSTRACT FROM AUTHOR]

Patients with heart failure with preserved ejection fraction (HFpEF) universally complain of exercise intolerance and dyspnoea as key clinical correlates. Cardiac as well as extracardiac components play a role for the limited exercise capacity, including an impaired cardiac and peripheral vascular reserve, a limitation in mechanical ventilation and/or gas exchange with reduced pulmonary vascular reserve, skeletal muscle dysfunction and iron deficiency/anaemia. Although most of these components can be differentiated and quantified through gas exchange analysis by cardiopulmonary exercise testing (CPET), the information provided by objective measures of exercise performance has not been systematically considered in the recent algorithms/scores for HFpEF diagnosis, by neither European nor US groups. The current clinical consensus statement by the Heart Failure Association (HFA) and European Association of Preventive Cardiology (EAPC) of the European Society of Cardiology (ESC) aims at outlining the role of exercise testing and its pathophysiological, clinical and prognostic insights, addressing the implications of a thorough functional evaluation from the diagnostic algorithm to the pathophysiology and treatment perspectives of HFpEF. Along with these goals, we provide a specific analysis of the evidence that CPET is the standard for assessing, quantifying, and differentiating the origin of dyspnoea and exercise impairment and even more so when combined with echocardiography and/or invasive haemodynamic evaluation. This will lead to improved quality of diagnosis when applying the proposed scores and may also help to implement the progressive characterization of the specific HFpEF phenotypes, a critical step toward the delivery of phenotype-specific treatments. [ABSTRACT FROM AUTHOR]

Aims: Obesity is a risk factor for heart failure with preserved ejection fraction (HFpEF), particularly in women, but the mechanisms remain unclear. The present study aimed to investigate the impact of central adiposity in patients with HFpEF and explore potential sex differences. Methods and results: A total of 124 women and 105 men with HFpEF underwent invasive haemodynamic exercise testing and rest echocardiography. Central obesity was defined as a waist circumference (WC) ≥88 cm for women and ≥102 cm for men. Exercise‐normalized pulmonary capillary wedge pressure (PCWP) responses were evaluated by the ratio of PCWP to workload (PCWP/W) and after normalizing to body weight (PCWL). The prevalence of central obesity (77%) exceeded that of general obesity (62%) defined by body mass index ≥30 kg/m2. Compared to patients without central adiposity, patients with HFpEF and central obesity displayed greater prevalence of diabetes and dyslipidaemia, higher right and left heart filling pressures and pulmonary artery pressures during exertion, and more severely reduced aerobic capacity. Associations between WC and fasting glucose, low‐density lipoprotein (LDL) cholesterol, peak workload, and pulmonary artery pressures were observed in women but not in men with HFpEF. Although increased WC was associated with elevated PCWP in both sexes, the association with PCWP/W was observed in women but not in men. The strength of correlation between PCWP/W and WC was more robust in women with HFpEF as compared to men (Meng's test p = 0.0008), and a significant sex interaction was observed in the relationship between PCWL and WC (p for interaction = 0.02). Conclusions: Central obesity is even more common than general obesity in HFpEF, and there appear to be important sexual dimorphisms in its relationships with metabolic abnormalities and haemodynamic perturbations, with greater impact in women. [ABSTRACT FROM AUTHOR]

The goal of this paper is to provide updated diagnostic criteria for the epilepsy syndromes that have a variable age of onset, based on expert consensus of the International League Against Epilepsy Nosology and Definitions Taskforce (2017–2021). We use language consistent with current accepted epilepsy and seizure classifications and incorporate knowledge from advances in genetics, electroencephalography, and imaging. Our aim in delineating the epilepsy syndromes that present at a variable age is to aid diagnosis and to guide investigations for etiology and treatments for these patients. [ABSTRACT FROM AUTHOR]

This then begs the question as to whether these NCD patients with latent PVD are truly "'normal' - they had poorer RV function during exercise compared to NCD patients without PVD, also resulting in underfilling of the left atrium, similar to HFpEF. Collectively, the evidence to date suggests that latent PVD is pathophysiologically important in HFpEF, just like more conventionally defined PVD at rest, and identification of patients with latent PVD may be important for phenotyping and patient selection for clinical trials. B This article refers to 'Concomitant latent pulmonary vascular disease leads to impaired global cardiac performance in heart failure with preserved ejection fraction' by A. Schuster I et al i ., published in this issue on pages 322-331. b Patients with heart failure (HF) and preserved ejection fraction (HFpEF) first present haemodynamically with left atrial hypertension at rest or with exercise, causing post-capillary pulmonary hypertension (PH). [Extracted from the article]

B P1 b B Exploring alpha-synuclein conformations by immunohistochemistry in Multiple System Atrophy and Parkinson's Disease b M. Otero Jimenez, J. Alegre Abarrategui and V. de Paola I Imperial College London, London, UK i Synucleinopathies include neurodegenerative diseases such as Parkinson's Disease (PD) and Multiple System Atrophy (MSA) characterised by the accumulation of pathological alpha-synuclein ( -syn) aggregates. Synucleinopathies differ in the extent of glial versus neuronal pathology; for instance, MSA is characterised by the presence of -syn aggregates in oligodendrocytes whereas PD mainly present -syn pathology in neurons. B P5 b B Microarray approach to identifying the role of microglia in the pathogenesis of age-associated deep-subcortical white matter lesions b T. Almansouri SP 1,2 sp , P. Heath SP 1 sp , S. Wharton SP 1 sp , F. Van Eeden SP 1 sp and J. Simpson SP 1 sp SP 1 sp I University of Sheffield, Sheffield, UK; i SP 2 sp I King Abdul-Aziz University, Jeddah, Saudi Arabia i B Introduction: b Age-associated deep-subcortical white matter lesions (DSCL) are an independent risk factor for dementia and contain high levels of CD68+ microglia. B Conclusions: b Whilst the brainstem demonstrates a disease-independent high susceptibility to inflammation, microglial activation in COVID-19 (COVID-19 microglia encephalopathy) is specific and of importance for understanding the involvement of the CNS in this disease. [Extracted from the article]

The heart failure epidemic is growing and its prevention, in order to reduce associated hospital readmission rates and its clinical and economic burden, is a key issue in modern cardiovascular medicine. The present position paper aims to provide practical evidence-based information to support the implementation of effective preventive measures. After reviewing the most common risk factors, an overview of the population attributable risks in different continents is presented, to identify potentially effective opportunities for prevention and to inform preventive strategies. Finally, potential interventions that have been proposed and have been shown to be effective in preventing heart failure are listed. [ABSTRACT FROM AUTHOR]

Egg consumption is one of the many inconsistencies in evidence linking dietary cholesterol to cardiovascular disease (CVD). In addition, the gut microbiota and its metabolite, trimethylamine‐N‐oxide (TMAO), have been shown to play a crucial role in the development of CVD. The fact that egg is rich in choline suggests that excessive egg consumption may increase TMAO production by altering the gut microbiota. However, the effects of egg consumption on vascular function and gut microbiota remain unclear. Here, the diet of nine young male subjects was supplemented with two boiled eggs daily for 2 weeks. Changes in vascular function, inflammation, metabolism, oxidative stress, and gut microbiota were examined. We found that egg consumption increased flow‐mediated dilation and decreased brachial‐ankle pulse wave velocity. Furthermore, egg consumption positively modulated the gut microbiota function but had no effects on the levels of C‐reactive protein, glucose, lipid profile, malondialdehyde, superoxide dismutase, or TMAO. The current study provides evidence that egg consumption improves vascular function, which may be related to the alterations seen in the gut microbiota. Therefore, moderate egg consumption may help to improve vascular and intestinal function in individuals at low risk of developing CVD and other metabolic disorders. [ABSTRACT FROM AUTHOR]

The heart failure epidemic is growing and its prevention, in order to reduce associated hospital readmission rates and its clinical and economic burden, is a key issue in modern cardiovascular medicine. The present position paper aims to provide practical evidence-based information to support the implementation of effective preventive measures. After reviewing the most common risk factors, an overview of the population attributable risks in different continents is presented, to identify potentially effective opportunities for prevention and to inform preventive strategies. Finally, potential interventions that have been proposed and have been shown to be effective in preventing heart failure are listed. [ABSTRACT FROM AUTHOR]

Objective. We evaluated the effects and mechanisms of GDC0623 on osteogenic differentiation of osteoblasts induced by IL-1β. Methodology. Osteoblasts were treated with 20 ng/ml IL-1β and 0.1 µM GDC0623. Cell proliferation levels were evaluated by the cell counting kit 8 (CCK8), EdU assay, and western blotting [proliferating cell nuclear antigen (PCNA) and Cyclin D1]. Osteoblasts were cultured in an osteogenic induction medium for 1–3 weeks after which their differentiations were assessed by alkaline phosphatase (ALP) staining, Alizarin Red staining, calcium concentration, immunocytochemistry staining, real-time quantitative PCR (RT-qPCR), and immunofluorescence staining. The osteogenesis-associated mechanisms were further evaluated by western blotting using appropriate antibodies. Results. Relative to the control group, IL-1β induced the rapid proliferation of osteoblasts and suppressed their osteogenic differentiations by upregulating the activities of MEK-Erk1/2 as well as Jak-Stat3 pathways and by elevating MMP13 and MMP9 levels. However, blocking of the MEK-Erk1/2 signaling pathway by GDC0623 treatment reversed these effects. Conclusion. Inhibition of Jak-Stat3 pathway by C188-9 downregulated the expression levels of MMP9 and MMP13, activated MEK-Erk1/2 pathway, and inhibited osteogenic differentiation. [ABSTRACT FROM AUTHOR]

Heart failure with preserved ejection fraction (HFpEF) will soon take over as the predominant form of heart failure. This is largely driven by the continuing increased incidences of obesity and type 2 diabetes (T2D), which promote HFpEF in the absence of pressure overload stresses. With beta‐blockers showing little effectiveness in treating obesity/T2D HFpEF and with no HFpEF‐targeted drugs currently available, we are in urgent need of a better understanding of how obesity/T2D HFpEF develops and how we may treat this condition. An exciting emerging field aiming to do this focuses on the investigation of 3',5'‐cyclic adenosine monophosphate (cAMP) microdomains in the heart. The previous work has largely focused on the investigation of cAMP microdomain remodelling in heart failure with reduced ejection fraction (HFrEF), with this work uncovering potential new targets for intervention strategies that otherwise would have been overlooked when studying changes in cAMP dynamics at the whole‐cell level. In this review, we aimed to discuss current advancements in our understanding of cAMP microdomain remodelling in HFrEF vs that in obesity/T2D‐associated HFpEF, with particular focus on the unresolved questions and limitations we face in being able to translate this knowledge. [ABSTRACT FROM AUTHOR]

Aims: Circulating blood volume is functionally divided between the unstressed volume, which fills the vascular space, and stressed blood volume (SBV), which generates vascular wall tension and intravascular pressure. With decreases in venous capacitance, blood functionally shifts to the SBV, increasing central venous pressure and pulmonary venous pressures. Obesity is associated with both elevated venous pressure and heart failure with preserved ejection fraction (HFpEF). To explore the mechanisms underlying this association, we evaluated relationships between blood volume distribution, venous compliance, and body mass in patients with and without HFpEF.Methods and Results: Subjects with HFpEF (n = 62) and non-cardiac dyspnoea (NCD) (n = 79) underwent invasive haemodynamic exercise testing with echocardiography. SBV was estimated (eSBV) from measured haemodynamic variables fit to a comprehensive cardiovascular model. Compared to NCD, patients with HFpEF displayed a leftward-shifted central venous pressure-dimension relationship, indicating reduced venous compliance. eSBV was 81% higher at rest and 69% higher during exercise in HFpEF than NCD (both P < 0.0001), indicating reduced venous capacitance. Despite greater augmented eSBV with exercise, the increase in cardiac output was reduced in HFpEF, suggesting operation on the plateau of the Starling curve. Exercise eSBV was directly correlated with higher body mass index (r = 0.77, P < 0.0001) and inversely correlated with right ventricular-pulmonary arterial coupling (r = -0.57, all P < 0.0001).Conclusions: Patients with HFpEF display reductions in systemic venous compliance and increased eSBV related to reduced venous capacitance, abnormalities in right ventricular-pulmonary artery interaction, and increased body fat. These data provide new evidence supporting an important role of venous dysfunction in obesity-related HFpEF and suggest that therapies that improve venous function may hold promise to improve clinical status in this cohort. [ABSTRACT FROM AUTHOR]

Aims: Inappropriate control of blood volume redistribution may be a mechanism responsible for exercise intolerance in heart failure with preserved ejection fraction (HFpEF). We propose to address this underlying pathophysiology with selective blockade of sympathetic signalling to the splanchnic circulation by surgical ablation of the right greater splanchnic nerve (GSN). Methods and results: In a single‐arm, prospective, two‐centre trial, 10 patients with HFpEF (50% male, mean age 70 ± 3 years) all with New York Heart Association (NYHA) class III, left ventricular ejection fraction >40%, pulmonary capillary wedge pressure (PCWP) ≥15 mmHg at rest or ≥25 mmHg with supine cycle ergometry, underwent ablation of the right GSN via thoracoscopic surgery. Patients were evaluated at baseline, 1, 3, 6 and 12 months after the procedure. The primary endpoint was a reduction in exercise PCWP at 3 months. There were no adverse events related to the blockade of the nerve during 12‐month follow‐up but three patients had significant peri‐procedural adverse events related to the surgical procedure itself. At 3 months post‐GSN ablation, patients demonstrated a reduction in 20 W exercise PCWP when compared to baseline [−4.5 mmHg (95% confidence interval, CI −14 to −2); P = 0.0059], which carried over to peak exercise [−5 mmHg (95% CI −11 to 0; P = 0.016). At 12 months, improvements were seen in NYHA class [3 (3) vs. 2 (1, 2); P = 0.0039] and quality of life assessed with the Minnesota Living with Heart Failure Questionnaire [60 (51, 71) vs. 22 (16, 27); P = 0.0039]. Conclusion: In this first‐in‐human study, GSN ablation in HFpEF proved to be feasible, with a suggestion of reduced cardiac filling pressure during exercise, improved quality of life and exercise capacity. [ABSTRACT FROM AUTHOR]