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Elevated nocturnal blood pressure (BP) is closely associated with increased risk of cardiovascular (CV) events. Circulating extracellular vesicles (EVs) have been proposed as a potential CV risk biomarker and shown to correlate with BP. The present study aimed to assess whether a reduction in BP is paralleled by respective changes in EVs.Fifty-five hypertensive patients (age: 57.7 ± 14.1 years) were included in the study. EVs and BP were assessed at baseline and at 12 weeks follow-up. Interventions to lower BP included advice on life-style modification only or life-style advice combined with additional pharmacotherapy. EVs were evaluated by flow cytometry (CD41+/Annexin V+) and BP by unobserved automated office BP and ambulatory BP monitoring.Nocturnal systolic BP correlated with EV levels at baseline ( P = 0.01). Multivariable regression models showed that changes in nocturnal systolic BP (adjusted R2 = 0.23; P = 0.01) and diastolic BP (adjusted R2 = 0.18; P = 0.02) were associated with respective changes in EV levels. Furthermore, intervention-induced improvement of systolic dipping was associated with a reduction in EVs in the univariate analysis (adjusted R2 = 0.06; P = 0.03). In contrast, systolic office, 24 h- and daytime-BP did not show significant associations with EVs. Patients whose medication was up-titrated at baseline showed a trend towards lower EV levels at follow-up (absolute change of -1.7 ± 1.3 EV/μl; P = 0.057).Circulating platelet-derived EVs were positively associated with nocturnal BP and therapy-induced changes over a 12-week treatment period. EVs may provide an integrated measure of BP changes achieved with pharmacotherapy.

OBJECTIVEWe analyzed whether any change in capillary density in the retinal circulation could be detected in patients with hypertension in the prediabetic stage.RESEARCH DESIGN AND METHODSIn a cross-sectional analysis, we assessed capillary density in the foveal (CDF) and parafoveal retinal areas using optical coherence tomography-angiography in 62 patients with hypertension and normal glucose metabolism and 40 patients with hypertension and prediabetes.RESULTSThe CDF was lower in patients with prediabetes than in those with normal glucose metabolism. Moreover, we found a correlation between CDF and HbA1c and glucose levels for the entire cohort. In patients with HbA1c CONCLUSIONSPatients with hypertension and prediabetes display retinal capillary changes, and an association with markers of glucose metabolism exists, even within a nondiabetic HbA1c range.

Introduction The concept of targeting the renal sympathetic nerves therapeutically to lower blood pressure (BP) is based on their crucial role in regulating both renal and cardiovascular control. These effects are mainly mediated via three major mechanisms including alteration of renal blood flow, renin-release, and Na+ retention. Initial surgical approaches applying crude and unselected sympathectomy, while rendering significant BP lowering and cardiovascular event reducing properties, where plagued by side effects. More modern selective catheter-based denervation approaches selectively targeting the renal nerves have been shown to be safe and effective in reducing BP in various forms of hypertension and multiple comorbidities. Areas covered This article covers the background relevant for the concept of renal denervation (RDN), the evidence obtained from relevant randomized controlled trials to substantiate the safety and efficacy of RDN, and recently published clinical recommendations. Expert opinion Catheter-based RDN is safe and has now been shown in sham-controlled randomized clinical trials to result in clinically meaningful BP lowering in both drug naive hypertensive patients and those on concomitant antihypertensive therapy. Real world data from a large global registry further supports the clinical utility of RDN. It now seems time to embed renal denervation into routine clinical care.

Recent analysis of systolic inter-arm differences in blood pressure from the INTERPRESS-IPD Collaboration suggest an association with increased all-cause mortality, cardiovascular mortality and cardiovascular events. Previous studies have demonstrated associations with other risk parameters. We aimed to reproduce these associations in a cohort of 199 treated, at-risk hypertensive patients with pulse wave velocity (PWV) as a surrogate marker of cardiovascular (CV) damage. Simultaneously measured inter-arm blood pressure (BP) differences, 24 hour ambulatory BP and PWV were measured in 199 treated patients from a tertiary hospital hypertension outpatient clinic. Associations between systolic inter-arm BP difference and PWV were analyzed with uni- and multi-variate regression models. Out of 199 participants, 90 showed an inter-arm BP difference of more than 5 mmHg. The inter-arm difference was not associated with PWV. Furthermore, neither observed single BP measurements nor 24 hour ambulatory BP was associated with inter-arm BP differences. In our clinical patient cohort we failed to observe an association between inter-arm BP differences and PWV. Mode of assessment, study design and the sample characteristics of this treated, hypertensive cohort may have contributed to the negative findings. The limited sample size of the study poses a challenge to the detection of smaller effects in our study.

Introduction Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a relatively novel glucose-lowering drugs (GLDs) which additionally promote weight loss and blood pressure reduction amongst other beneficial effects. Areas covered This review reflects on the extra-glycaemic effects of SGLT2 inhibitors and their impact on important clinical endpoints, and provides an overview of data relating to a newer member of the SGLT2 inhibitor class, bexagliflozin. Expert opinion SGLT2 inhibitors, while consolidating glycaemic control as adjunctive therapy, indisputably effect cardio-renal benefits in the T2D population which is prevalently afflicted by heightened cardiovascular risk profiles and a disproportionately increased incidence of unfavourable cardiovascular and renal clinical outcomes. The data from landmark trials demonstrate that beneficial effects of SGLT2 inhibitors extend to non-diabetic patients with chronic kidney disease (CKD) and/or heart failure with reduced ejection fraction (HFrEF). Preliminary findings from the BEST trial suggest that Bexagliflozin's effects reflect those of other licensed drugs in its class. Bexagliflozin has also been shown to be safe and effective in patients with diabetes and CKD stage 3b. If and when approved, it presents physicians with the prospect of an additional therapeutic option in managing patients with type 2 diabetes mellitus (T2D), and conceivably also, nondiabetic patients with established CKD and/or HFrEF.

Hypertension is the most common chronic condition globally, contributing to an increased risk of cardiovascular disease and premature death. Despite advances in treatment options, approximately 10% of patients have resistant hypertension, characterized by elevated blood pressure that does not respond to treatment. The gut microbiome is now increasingly recognized to play a role in the development and pathogenesis of several diseases, including hypertension, although the exact mechanisms remain unclear.The aim of the present study was to investigate circulating levels of short-chain fatty acids, metabolites produced by gut bacteria, in essential ( n = 168) and resistant hypertensive ( n = 27) patients, compared with healthy controls ( n = 38).Serum acetate was significantly lower in the resistant hypertensive population, compared with both the normotensive controls and those with essential hypertension (748 ± 89 versus 1335 ± 61 and 1171 ± 22 nmol/ml, P 0.0001). Acetate was also significantly lower in treated versus untreated hypertensive patients or controls (1112 ± 27 versus 1228 ± 40 and 1327 ± 63 nmol/l, P 0.01), with this finding more pronounced with increasing number of antihypertensive therapies. In contrast, propionate was lower and butyrate significantly higher in those with essential hypertension compared with controls (propionate: 25.2 ± 7.5 versus 58.6 ± 7.6 nmol/ml, P 0.0001; butyrate: 46.5 ± 3.5 versus 14.7 ± 9.9 nmol/ml, P 0.01). A novel and perhaps clinically relevant observation was the significant difference in acetate and propionate levels between patients taking ACE inhibitors or angiotensin-receptor blockers.The present study has highlighted differences in circulating short-chain fatty acids in different hypertensive phenotypes and a possible influence of drug number and class. Although further research is necessary, this may represent a novel therapeutic target, particularly in patients with resistant hypertension.

Microparticles are small cell vesicles that are derived from the cell membrane in response to different biological processes. There is growing evidence supporting the association between microparticles and cardiovascular disease, as their pathophysiology commonly includes endothelial damage and chronic inflammation which also promote a prothrombotic state. The direct causal link between the release of the different subtypes of microparticles and their implications on physiological and pathological conditions is still not completely elucidated. However, evidence suggests microparticles released from platelets, leukocytes, and endothelium may help to evaluate vascular health as they have a relevant role in inflammation, endothelial function, and thrombosis. This review aims to provide a short overview of the biogenesis, characteristics, and detection methodology of microparticles with a special focus on their possible implication in cardiovascular settings.

BACKGROUND A nocturnal non-dipping pattern has been associated with hypertension-mediated organ damage (HMOD), morbidity and mortality. Retinal imaging through application of modern technologies including optical coherence tomography angiography (OCT-A) can provide detailed insights into early vascular damage. In this observational study, we investigated the relationship of microscopic vascular density in the retina measured with OCT-A and nocturnal blood pressure (BP) dipping. METHODS Retinal OCT-A and ambulatory BP monitoring (ABPM) data prospectively obtained from 142 patients referred to a tertiary hypertension clinic were analysed with regression models for associations between BP night-time dipping and retinal capillary vascular density in three different zones around the fovea. RESULTS More pronounced nocturnal SBP and DBP dipping was significantly associated with increased vascular density in the central foveal area of the retina. These associations were robust to adjustment for other available risk factors including mean daytime BP. Parafoveal and whole image vascular density did not show equivalent significant associations with nocturnal BP dipping. The results were reproducible when assessed in a subgroup of patients who had concomitant type 2 diabetes. CONCLUSION Foveal vascular density was associated with the nocturnal BP dipping pattern in hypertensive patients. These associations were robust to adjustment of relevant factors such as daytime BP. Our findings highlight the importance of nocturnal BP features reflected in ambulatory BP monitoring in the assessment of HMOD. Whether routine assessment of retinal damage markers may improve risk management of hypertensive patients remains to be determined.

Background Positional changes in blood pressure (BP) have been shown to have effects on long-term outcomes. Although a BP drop with upright posture is frequently observed, an orthostatic rise in BP can also occur. Here, we aimed to investigate whether the phenotype of orthostatic hypertension is associated with more pronounced vascular hypertension-mediated organ damage (HMOD) and whether this is associated with other cardiovascular risk factors. Methods In a cohort of 200 patients referred to our tertiary hypertension clinic, we prospectively assessed unattended seated automated office BP and the response to 1 min of upright posture. The difference in BP after standing up was calculated and pulse wave velocity (PWV) was assessed as a marker of vascular HMOD. Routine clinical cardiovascular risk markers were also assessed. Regression models were used to assess the association between orthostatic BP changes and pulse wave velocity. Results Baseline characteristics and clinic cardiovascular risk factors were similar between orthostatic BP response groups. A U-shaped association was evident between PWV and orthostatic BP changes with elevated PWV in patients with either a fall or a rise in BP in response to upright posture. The regression models remained significant after adjusting for other cardiovascular risk factors, including 24 h ambulatory BP. Conclusion Both an orthostatic BP drop and rise were associated with elevated PWV. Although standing BP is commonly measured in elderly hypertensive patients to exclude significant orthostatic hypotension, this simple measurement may provide an additional independent risk factor for vascular HMOD at any age.

Patients with progressing chronic kidney disease (CKD) are more likely to experience cardio‐ and cerebrovascular events than progressing to end‐stage renal disease. The authors explored whether retinal microvascular calibers differed with the degree of renal impairment and between the standard and extended optic disk and may serve as a simple additional tool for risk stratification in this highly vulnerable patient cohort. The authors analyzed central retinal arteriolar and venular equivalent calibers (CRAE, CRVE) at different retinal zones (zone B&C) using digital retinal imaging in hypertensive patients with stage 2 (n = 66) or stage 3 CKD (n = 30). Results were adjusted for age, sex, HbA1c, and 24‐hour diastolic blood pressure. Mean eGFR was 77.7 ± 8.9 and 48.8 ± 7.9 ml/min/1.73 m2 for stage 2 and 3 CKD, respectively. CRAE and CRVE in zones B and C were significantly lower in patients with stage 3 CKD compared to patients with stage 2 CKD (CRAE‐B:141.1 ± 21.4 vs. 130.5 ± 18.9 µm, p = .030; CRAE‐C:137.4 ± 19.4 vs 129.2 ± 18.2 µm, p = .049; CRVE‐B:220.8 ± 33.0 vs. 206.0 ± 28.4 µm, p = .004; and CRVE‐C:215.9 ± 33.0 vs. 201.2 ± 25.1µm, p = .003). In patients with stage 2 CKD, CRAE‐B was higher than CRAE‐C (141.1 ± 21.4 vs. 137.4 ± 19.4µm, p

Elevated circulating platelet-derived extracellular vesicles (EVs) have been reported in conditions associated with thrombotic risk. The present study aimed to assess the relationship between circulating platelet-derived EV levels, cardiovascular risk stratification and vascular organ damage, as assessed by pulse wave velocity (PWV). A total of 92 patients were included in the present analysis. Platelet EV were evaluated by flow cytometry (CD41+/Annexin v+). The cardiovascular risk was determined using the 2021 ESC guideline stratification and SCORE2 and SCORE-OP. PWV was performed as a surrogate to assess macrovascular damage. Risk stratification revealed significant group differences in EV levels (ANOVA, p = 0.04). Post hoc analysis demonstrated significantly higher levels of EVs in the very high-risk group compared with the young participants (12.53 ± 8.69 vs. 7.51 ± 4.67 EV/µL, p = 0.03). Linear regression models showed SCORE2 and SCORE-OP (p = 0.04) was a predictor of EV levels. EVs showed a significant association with macrovascular organ damage measured by PWV (p = 0.01). PWV progressively increased with more severe cardiovascular risk (p < 0.001) and was also associated with SCORE2 and SCORE-OP (p < 0.001). Within the pooled group of subjects with low to moderate risk and young participants (

Machine Learning is transforming data processing in medical research and clinical practice. Missing data labels are a common limitation to training Machine Learning models. To overcome missing labels in a large dataset of microneurography recordings, a novel autoencoder based semi-supervised, iterative group-labelling methodology was developed.Autoencoders were systematically optimised to extract features from a dataset of 478621 signal excerpts from human microneurography recordings. Selected features were clusters with k-means and randomly selected representations of the corresponding original signals labelled as valid or non-valid muscle sympathetic nerve activity (MSNA) bursts in an iterative, purifying procedure by an expert rater. A deep neural network was trained based on the fully labelled dataset.Three autoencoders, two based on fully connected neural networks and one based on convolutional neural network, were chosen for feature learning. Iterative clustering followed by labelling of complete clusters resulted in all 478621 signal peak excerpts being labelled as valid or non-valid within 13 iterations. Neural networks trained with the labelled dataset achieved, in a cross validation step with a testing dataset not included in training, on average 93.13% accuracy and 91% area under the receiver operating curve (AUC ROC).The described labelling procedure enabled efficient labelling of a large dataset of physiological signal based on expert ratings. The procedure based on autoencoders may be broadly applicable to a wide range of datasets without labels that require expert input and may be utilised for Machine Learning applications if weak-labels were available.

BACKGROUND Renal denervation (RDN) has been proven in multiple sham-controlled trials to lower blood pressure (BP) in various forms of hypertension. RDN-mediated interruption of sympathetic signaling through its effects on renal blood flow, salt retention, and renin release are likely contributors to the BP-lowering effects. However, the impact of RDN on salt sensitivity in humans has not yet been explored. METHODS We, therefore, investigated the effect of RDN on ambulatory BP monitoring-derived salt sensitivity in a cohort of patients with uncontrolled hypertension on habitual salt intake. RDN was performed in 153 hypertensive patients, who were categorized into low intermediate and high-salt sensitivity groups, based on the ambulatory BP monitoring-derived salt sensitivity index estimated prior to (baseline) and at 3, 6 and 12 months after the procedure as previously described. Crude and adjusted mixed effects ordinal regression models were fitted to test for changes in the proportions of salt sensitivity risk during follow-up. RESULTS The proportions of individuals in the intermediate and high-salt sensitivity risk group increased after RDN and the odds for being in a higher estimated salt sensitivity risk group at 3, 6 and 12 months follow-up compared with baseline were highly significant during the 12 months follow-up period. CONCLUSION Increased salt sensitivity after RDN may represent a compensatory mechanism to maintain renal capacity for adequate salt handling. This novel finding may have implications for patient management after RDN, such as prescription of salt moderation to further optimize RDN-induced BP-lowering efficacy.

Automated analysis and quantification of physiological signals in clinical practice and medical research can reduce manual labor, increase efficiency, and provide more objective, reproducible results. To build a novel platform for the analysis of muscle sympathetic nerve activity (MSNA), we employed state‐of‐the‐art data processing and machine learning applications. Data processing methods for integrated MSNA recordings were developed to evaluate signals regarding the overall quality of the signal, the validity of individual signal peaks regarding the potential to be MSNA bursts and the timing of their occurrence. An overall probability score was derived from this flexible platform to evaluate each individual signal peak automatically. Overall, three deep neural networks were designed and trained to validate individual signal peaks randomly sampled from recordings representing only electrical noise and valid microneurography recordings. A novel data processing method for the whole signal was developed to differentiate between periods of valid MSNA signal recordings and periods in which the signal was not available or lost due to involuntary movement of the recording electrode. A probabilistic model for timing of the signal bursts was implemented as part of the system. Machine Learning algorithms and data processing tools were implemented to replicate the complex decision‐making process of manual MSNA analysis. Validation of manual MSNA analysis including intra‐ and inter‐rater validity and a comparison with automated MSNA tools is required. The developed toolbox for automated MSNA analysis can be extended in a flexible way to include algorithms based on other datasets., Machine Learning algorithms and data processing tools were implemented to replicate the complex decision making process of manual MSNA analysis. Validation of manual MSNA analysis including intra‐ and inter‐rater validity and a comparison with automated MSNA tools is required. The developed toolbox for automated MSNA analysis can be extended in a flexible way to include algorithms based on other datasets.

Homocysteine is an independent risk factor for cardiovascular and cerebrovascular disease and has been proposed to contribute to vascular dysfunction. We sought to determine in a real‐world clinical setting whether homocysteine levels were associated with hypertension mediated organ damage (HMOD) and could guide treatment choices in hypertension. We performed a cross‐sectional analysis of prospectively collected data in 145 hypertensive patients referred to our tertiary hypertension clinic at Royal Perth Hospital and analyzed the association of homocysteine with HMOD, renin‐angiotensin‐aldosterone system (RAAS), and RAAS blockade. The average age of participants was 56 ± 17 years, and there was a greater proportion of males than females (89 vs. 56). Regression analysis showed that homocysteine was significantly associated with PWV (β = 1.99; 95% CI 0.99‐3.0; p

Background/Introduction Recent analysis of systolic inter-arm differences in blood pressure from the INTERPRESS-IPD Collaboration suggest an association with increased all-cause mortality, cardiovascular mortality and cardiovascular events, previous studies have demonstrated associations with other risk parameters. Purpose We aimed to reproduce these associations in a cohort of 199 treated, at-risk, hypertensive patients with pulse wave velocity (PWV) as a surrogate marker of cardiovascular (CV) damage. Methods Simultaneously measured Inter-arm blood pressure differences, 24 hour ambulatory BP and PWV were measured in 199 treated patients of a tertiary hospital hypertension outpatient clinic. Associations between systolic inter-arm BP difference and PWV were analyzed with uni- and multivariate regression models. Results Out of 199 participants, 90 showed an Inter-arm blood pressure difference of more than 5 mmHg. The Inter-arm difference was not associated with PWV. Furthermore, neither observed single blood pressure measurements nor 24 hour ambulatory blood pressure was associated with Inter-arm blood pressure differences. Conclusion In our clinical patient cohort we failed to observe an association between inter-arm BP differences and PWV. Mode of assessment, study design or the sample characteristics of this treated, hypertensive cohort may explain the negative results. The limited sample size of the study poses a challenge to the detection of smaller effects in our study. Funding Acknowledgement Type of funding sources: None.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is the most common liver disease affecting a quarter of the global population and is often associated with adverse health outcomes. The increasing prevalence of MAFLD occurs in parallel to that of metabolic syndrome (MetS), which in fact plays a major role in driving the perturbations of cardiometabolic homeostasis. However, the mechanisms underpinning the pathogenesis of MAFLD are incompletely understood. Compelling evidence from animal and human studies suggest that heightened activation of the sympathetic nervous system is a key contributor to the development of MAFLD. Indeed, common treatment strategies for metabolic diseases such as diet and exercise to induce weight loss have been shown to exert their beneficial effects at least in part through the associated sympathetic inhibition. Furthermore, pharmacological and device-based approaches to reduce sympathetic activation have been demonstrated to improve the metabolic alterations frequently present in patients with obesity, MetSand diabetes. Currently available evidence, while still limited, suggests that sympathetic activation is of specific relevance in the pathogenesis of MAFLD and consequentially may offer an attractive therapeutic target to attenuate the adverse outcomes associated with MAFLD.

Night‐time blood pressure (BP) is an important predictor of cardiovascular outcomes. Its assessment, however, remains challenging due to limited accessibility to ambulatory BP devices in many settings, costs, and other factors. We hypothesized that BP measured in a supine position during daytime may perform similarly to night‐time BP when modeling their association with vascular hypertension‐mediated organ damage (HMOD). Data from 165 hypertensive patients were used who as part of their routine clinic workup had a series of standardized BP measurements including seated attended office, seated and supine unattended office, and ambulatory BP monitoring. HMOD was determined by assessment of kidney function and pulse wave velocity. Correlation analysis was carried out, and univariate and multivariate models were fitted to assess the extent of shared variance between the BP modalities and their individual and shared contribution to HMOD variables. Of all standard non‐24‐hour systolic BP assessments, supine systolic BP shared the highest degree of variance with systolic night‐time BP. In univariate analysis, both systolic supine and night‐time BP were strong determinants of HMOD variables. In multivariate models, supine BP outperformed night‐time BP as the most significant determinant of HMOD. These findings indicate that supine BP may not only be a clinically useful surrogate for night‐time BP when ambulatory BP monitoring is not available, but also highlights the possibility that unattended supine BP may be more closely related to HMOD than other BP measurement modalities, a proposition that requires further investigations in prospective studies.

Objective Although the detrimental effect of increased mean blood pressure (BP) is well established, the role of the dynamic and circadian features of BP is less well defined but may be similarly important. In this prospective analysis of hypertensive patients from a tertiary hospital hypertension clinic, we investigated whether the presence of night-time systolic hypertension is associated with more pronounced end-organ damage as assessed by measures of pulse wave analysis (PWA) and pulse wave velocity (PWV). Methods A cohort of 222 consecutive hypertensive patients underwent ambulatory blood pressure measurements, PWA, PWV testing and collection of routine clinical data. Group differences and group-effects of daytime and night-time hypertension on target organ damage and cardiovascular risk parameters were analysed. Results Nocturnal hypertension was evident in more than half of the study population. PWV, central systolic, mean arterial and pulse pressure were higher in patients with nocturnal hypertension. Stratification into four groups according to daytime and night-time hypertension status revealed group differences in all outcome parameters. Posthoc testing for individual group differences demonstrated significant differences between fully controlled individuals and the group with high daytime and night-time BP. In a regression analysis for independent effects of categorical night-time and daytime hypertension, nocturnal hypertension was a significant predictor for all PWA and PWV outcomes. Conclusion Nocturnal hypertension was a highly prevalent phenotype in this population and associated with increased central BP and more pronounced target organ damage as indicated by elevated PWV. Regression analysis confirmed the role of night-time hypertension as an independent explanatory variable for elevated PWV.

Loin pain hematuria syndrome (LPHS) frequently presents with severe chronic pain that poses a clinical challenge. Current treatment approaches are mostly empirical and include a wide range of therapeutic strategies such as physical therapy, local and systemic analgesia, interventional and surgical approaches usually flanked by psycho-behavioral therapy, and other strategies. LPHS often impacts negatively on quality of life particularly in patients who are refractory to treatment. With recent advances in catheter-based treatment approaches and better understanding of the pathophysiology of LPHS, intraluminal renal denervation (RDN) has been proposed as a valuable treatment option for kidney-related pain syndromes. The present review provides a brief overview of the clinical challenges associated with LPHS, highlights recent insights into its underlying mechanisms, and summarizes currently available data on the use of RDN in the context of LPHS and kidney-related pain syndromes. Renal denervation via various approaches including surgical and catheter-based techniques has shown promise in alleviating kidney-related pain syndromes. Randomized controlled trials are now required to better define its role in the management of these conditions.

Studies have revealed a robust and independent correlation between chronic kidney disease (CKD) and cardiovascular (CV) events, including death, heart failure, and myocardial infarction. Recent clinical trials extend this range of adverse CV events, including malignant ventricular arrhythmias and sudden cardiac death (SCD). Moreover, other studies point out that cardiac structural and electrophysiological changes are a common occurrence in this population. These processes are likely contributors to the heightened hazard of arrhythmias in CKD population and may be useful indicators to detect patients who are at a higher SCD risk. Sympathetic overactivity is associated with increased CV risk, specifically in the population with CKD, and it is a central feature of the hypertensive state, occurring early in its clinical course. Sympathetic hyperactivity is already evident at the earliest clinical stage of CKD and is directly related to the progression of renal failure, being most pronounced in those with end-stage renal disease. Sympathetic efferent and afferent neural activity in kidney failure is a crucial facilitator for the perpetuation and evolvement of the disease. Here, we will revisit the role of the feedback loop of the sympathetic neural cycle in the context of CKD and how it may aggravate several of the risk factors responsible for causing SCD. Targeting the overactive sympathetic nervous system therapeutically, either pharmacologically or with newly available device-based approaches, may prove to be a pivotal intervention to curb the substantial burden of cardiac arrhythmias and SCD in the high-risk population of patients with CKD.

Background Accessibility of labelled datasets is often a key limitation for the application of Machine Learning in clinical research. A novel semi-automated weak-labelling approach based on unsupervised clustering was developed to classify a large dataset of microneurography signals and subsequently used to train a Neural Network to reproduce the labelling process. Methods Clusters of microneurography signals were created with k-means and then labelled in terms of the validity of the signals contained in each cluster. Only purely positive or negative clusters were labelled, whereas clusters with mixed content were passed on to the next iteration of the algorithm to undergo another cycle of unsupervised clustering and labelling of the clusters. After several iterations of this process, only pure labelled clusters remained which were used to train a Deep Neural Network. Results Overall, 334,548 individual signal peaks form the integrated data were extracted and more than 99.99% of the data was labelled in six iterations of this novel application of weak labelling with the help of a domain expert. A Deep Neural Network trained based on this dataset achieved consistent accuracies above 95%. Discussion Data extraction and the novel iterative approach of labelling unsupervised clusters enabled creation of a large, labelled dataset combining unsupervised learning and expert ratings of signal-peaks on cluster basis in a time effective manner. Further research is needed to validate the methodology and employ it on other types of physiologic data for which it may enable efficient generation of large labelled datasets.

Extracellular vesicles (EVs) represent a promising biomarker in several medical areas. Flow cytometry (FC) is one of the most widely-used methods to characterize EVs, providing quantitative information and determination of EV subtypes. EV evaluation represents a challenge as no standardized methods are available to facilitate assessment across different research centers. This is principally because their size falls below the detection limit of most standard flow cytometers and a thorough optimization process is required to ensure instrument-specific sensitivity. We provide an overview of a standardized method to evaluate large EVs using the Attune™ Nxt Acoustic Focusing Flow Cytometer system (Thermo Fisher Scientific).

To review the findings of trials evaluating pharmacological treatment approaches for hypertension in general, and resistant hypertension (RH) in particular, and propose future research and clinical directions. RH is defined as blood pressure (BP) that remains above target levels despite adherence to at least three antihypertensive medications, including a diuretic. Thus far, clinical trials of pharmacological approaches in RH have focused on older molecules, with spironolactone being demonstrated as the most efficacious fourth-line agent. However, the use of spironolactone in clinical practice is hampered by its side effect profile and the risk of hyperkalaemia in important RH subgroups, such as patients with moderate-severe chronic kidney disease (CKD). Clinical trials of new molecules targeting both well-established and more recently elucidated pathophysiologic mechanisms of hypertension offer a multitude of potential treatment avenues that warrant further evaluation in the context of RH. These include selective mineralocorticoid receptor antagonists (MRAs), aldosterone synthase inhibitors (ASIs), activators of the counterregulatory renin-angiotensin-system (RAS), vaccines, neprilysin inhibitors alone and in combined formulations, natriuretic peptide receptor agonists A (NPRA-A) agonists, vasoactive intestinal peptide (VIP) agonists, centrally acting aminopeptidase A (APA|) inhibitors, antimicrobial suppression of central sympathetic outflow (minocycline), dopamine β-hydroxylase (DβH) inhibitors and Na+/H+ Exchanger 3 (NHE3) inhibitors. There is a paucity of data from trials evaluating newer molecules for the treatment of RH. Emergent novel molecules for non-resistant forms of hypertension heighten the prospects of identifying new, effective and well-tolerated pharmacological approaches to RH. There is a glaring need to undertake RH-focused trials evaluating their efficacy and clinical applicability.

"La plaqueta tiene un papel central en la iniciación, propagación y recurrencia del trombo dentro de los síndromes coronarios agudos y constituye la base para el empleo de agentes antiplaquetarios. Se ha descrito la influencia de polimorfismos genéticos del receptor P2Y12 en la respuesta a la activación plaquetaria entre los polimorfismos implicados se encuentran rs6809699, rs6785930 y rs2046934. El objetivo de este trabajo fue determinar la agregación plaquetaria en presencia de los SNP rs6809699, rs6785930 y rs2046934 en el receptor plaquetario P2Y12. Se analizaron 43 pacientes con enfermedad coronaria aguda bajo tratamiento antiplaquetario dual. Se determinó la agregación plaquetaria mediante el sistema VerifyNow la cual se cuantificó en unidades de reactividad plaquetaria (PRU) así como porcentaje de inhibición con fármaco antiplaquetario. La agregación plaquetaria fue de 31.8 ± 29.9 PRU (promedio±SD), con un porcentaje de inhibición de 81.9±17% (promedio±SD). Se determinó la presencia de los polimorfismos de nucleótido sencillo (SNP) rs6809699, rs6785930 y rs2046934 de 34 mediante PCR tiempo real utilizando TaqMan genotyping master mix. La frecuencia alélica para el alelo de alto riesgo fue: A) rs6809699: 14.5% B) rs6785930: 27.9% y C) rs2046934: 14.7%. Se compararon los valores de agregación plaquetaria en relación al genotipo presentado. Los pacientes heterocigotos mostraron mayor reactividad plaquetaria comparada con los homocigotos para el alelo ancestral. Los pacientes con presencia de dos o más alelos de alto riesgo muestran una tendencia numérica a mayor agregación plaquetaria."

Cardiovascular diseases (CVDs) have been considered the most predominant cause of death and one of the most critical public health issues worldwide. In the past two decades, cardiovascular (CV) mortality has declined in high-income countries owing to preventive measures that resulted in the reduced burden of coronary artery disease (CAD) and heart failure (HF). In spite of these promising results, CVDs are responsible for ~17 million deaths per year globally with ~25% of these attributable to sudden cardiac death (SCD). Pre-clinical data demonstrated that renal denervation (RDN) decreases sympathetic activation as evaluated by decreased renal catecholamine concentrations. RDN is successful in reducing ventricular arrhythmias (VAs) triggering and its outcome was not found inferior to metoprolol in rat myocardial infarction model. Registry clinical data also suggest an advantageous effect of RDN to prevent VAs in HF patients and electrical storm. An in-depth investigation of how RDN, a minimally invasive and safe method, reduces the burden of HF is urgently needed. Myocardial systolic dysfunction is correlated to neuro-hormonal overactivity as a compensatory mechanism to keep cardiac output in the face of declining cardiac function. Sympathetic nervous system (SNS) overactivity is supported by a rise in plasma noradrenaline (NA) and adrenaline levels, raised central sympathetic outflow, and increased organ-specific spillover of NA into plasma. Cardiac NA spillover in untreated HF individuals can reach ~50-fold higher levels compared to those of healthy individuals under maximal exercise conditions. Increased sympathetic outflow to the renal vascular bed can contribute to the anomalies of renal function commonly associated with HF and feed into a vicious cycle of elevated BP, the progression of renal disease and worsening HF. Increased sympathetic activity, amongst other factors, contribute to the progress of cardiac arrhythmias, which can lead to SCD due to sustained ventricular tachycardia. Targeted therapies to avoid these detrimental consequences comprise antiarrhythmic drugs, surgical resection, endocardial catheter ablation and use of the implantable electronic cardiac devices. Analogous NA agents have been reported for single photon-emission-computed-tomography (SPECT) scans usage, specially the 123I-metaiodobenzylguanidine (123I-MIBG). Currently, HF prognosis assessment has been improved by this tool. Nevertheless, this radiotracer is costly, which makes the use of this diagnostic method limited. Comparatively, positron-emission-tomography (PET) overshadows SPECT imaging, because of its increased spatial definition and broader reckonable methodologies. Numerous ANS radiotracers have been created for cardiac PET imaging. However, so far, [11C]-meta-hydroxyephedrine (HED) has been the most significant PET radiotracer used in the clinical scenario. Growing data has shown the usefulness of [11C]-HED in important clinical situations, such as predicting lethal arrhythmias, SCD, and all-cause of mortality in reduced ejection fraction HF patients. In this article, we discussed the role and relevance of novel tools targeting the SNS, such as the [11C]-HED PET cardiac imaging and RDN to manage patients under of SCD risk.

The non-Hodgkin lymphoma is a neoplastic entity that presents in extranodal form in 20 % of cases, usually occurs as solitary or generalized lymphadenopathy. There may be misdiagnosis if it manifests as primary extranodal disease because the primary infiltration may occur with different organs, despite the difficulty of diagnosis of primary extranodal location of non-Hodgkin lymphoma, histological and immunohistochemical studies are effective in preventing misdiagnosis. The presentation of this case is to describe this condition in its extranodal variety with cardiac infiltration in a 23 year-old woman with progressive dyspnea. Tumor mass was detected in right-atrial, venous catheterization biopsy was performed, this enabled the histopathological diagnosis and establish treatment. We present experiences from the attention of the case and review of the literature with special reference to diagnosis and treatment.El linfoma no Hodgkin es una entidad neoplásica que puede presentarse extraganglionarmente en el 20 % de los casos, habitualmente se presenta como linfadenopatía solitaria o generalizada. Se puede presentar error en el diagnóstico si se manifiesta enfermedad primaria extraganglionar ya que pueden presentarse con infiltración primaria a diferentes órganos, a pesar de la dificultad del diagnóstico de linfoma no Hodgkin de localización primaria extraganglionar, los estudios histológicos e inmunohistoquímicos son efectivos a la hora de evitar un diagnóstico erróneo. La presentación de este caso tiene como objetivo describir este padecimiento en su variedad extraganglionar con infiltración cardiaca en una paciente de 23 años que debutó con disnea progresiva. Se detectó una masa tumoral intraauricular derecha, por lo que se realizó biopsia por cateterismo venoso, que permitió hacer el diagnóstico histopatológico y establecer el tratamiento. Se presentan las experiencias derivadas de la atención del caso y revisión de la literatura médica con especial referencia al diagnóstico y tratamiento.

This paper describes the opportunities and challenges in building ST-elevation acute myocardial infarction (STEMI) systems of care in Stent for Life affiliated and collaborating so-called emerging countries, namely India, China, South Africa and Mexico, where CAD mortality is increasing and becoming a significant healthcare problem. The Stent for Life model supports the implementation of ESC STEMI Guidelines in Europe and endeavours to impact on morbidity and mortality by improving services and developing regional STEMI systems of care, whereby STEMI patients' timely access to a primary percutaneous coronary intervention (PPCI) is assured. In India, the STEMI India model incorporates a dual approach of combining PPCI with a pharmacoinvasive strategy of reperfusion. The architecture of the system is based on a hub and spoke model with each unit called a STEMI cluster. The project is driven by a private non-profit organisation. In China, the STEMI PCI programme is led by the Chinese College of Cardiovascular Physicians and supported by the national government. Although primary PCI is performed nationwide, a thrombolytic treatment strategy is still the first option in many rural areas because of logistic considerations. Establishing local STEMI transfer networks and then implementing a pharmacoinvasive strategy of reperfusion are being considered and promoted currently. In South Africa, the pharmacoinvasive approach currently dominates as STEMI treatment option in many areas. A pilot study shows that low symptom awareness leads to long patient delays. The education of all role players, from patients to healthcare professionals and including institutions and governmental structures, is needed to achieve prompt diagnosis and treatment. In Mexico, improving the treatment of STEMI requires considering myocardial infarction to be an emergency that must be treated by an entire system and not just by a particular service. Patients need to receive quick treatment from clinical and interventional cardiologists, and the emergency medical system (EMS) must understand the importance of early reperfusion therapy when appropriate. Mexican health authorities have used registries as their main strategy for improving the use of health resources for ACS patients. In general, building regional STEMI systems of care and an EMS system infrastructure are critical success factors in the stepwise development of STEMI systems of care at a national level in emerging countries as they are in Europe. An in-depth understanding of healthcare system-level barriers to timely and appropriate reperfusion therapy facilitates the development of more effective strategies for improving the quality of STEMI care in each region and country.

Cardiac tumors are rare entities in clinical practice, with an incidence of 0.05%. Approximately 75% are benign and 25% malignant. Among these, Lymphomas are uncommon, representing about 0.25%. The non-Hodgkin lymphomas can occur in extranodal tissues in 20% of the cases and 80% of these non-Hodgkin lymphomas are composed of diffuse B cells. The extranodal presentation is most frequent in young adults, with a high degree of malignancy and rapid growth. It can present with primary infiltration of various organs; cardiac involvement occurs in 20 to 28% of cases, usually located in the right chambers and with nonspecific symptoms, depending on the location and extent of the tumor. The diagnostic test in these cases is undoubtedly the biopsy of the lymph node or the affected tissue. We present the case of non-Hodgkin disease of diffuse large cells, with right intra-atrial involvement in a 23-year-old-female patient, who presented with progressive dyspnea. A transesophageal echocardiography was performed and an intra-atrial tumor mass was detected. A biopsy was performed, by femoral venous catheterization, allowing the establishment of the histopathological diagnosis and treatment. At a one year follow up, the patient shows complete remission.