Non-Invasive Assessment of Micro- and Macrovascular Function after Initiation of JAK Inhibitors in Patients with Rheumatoid Arthritis.

BACKGROUND: Janus kinase (JAK) inhibitors constitute a novel class of oral biologic disease-modifying antirheumatic drugs for patients with rheumatoid arthritis (RA). However, their use has been associated with increased risk of major cardiovascular events. We investigated whether treatment with JAK inhibitors exerts significant alterations in the micro- and microvasculature in RA patients. METHODS: Thirteen patients with RA initiating treatment with JAK inhibitors were prospectively studied. Eventually, data from 11 patients who completed the study were analyzed. Procedures were performed at baseline and 3 months after treatment. Nailfold videocapillaroscopy was applied to detect alterations of the dermal capillary network. Participants underwent 24 h ambulatory blood pressure monitoring (Mobil-O-Graph device) for the assessment of blood pressure (both brachial and aortic) and markers of large artery stiffening [pulse wave velocity (PWV), augmentation index] throughout the whole 24 h and the respective day- and nighttime periods. Carotid intima-media thickness was assessed with ultrasound. RESULTS: Three-month treatment with JAK inhibitors was not associated with any differences in brachial and aortic blood pressure, arterial stiffness, and carotid atherosclerosis, with the only exception of nighttime PWV, which was significantly elevated at follow-up. However, three-month treatment with JAK inhibitors induced significant microvascular alterations and increased the total number of capillaroscopic abnormalities. CONCLUSIONS: Three-month treatment with JAK inhibitors may exert significant effects on microcirculation as assessed with nailfold videocapillaroscopy, whereas macrovascular structure and function appears largely unaffected. Further research toward this direction may add substantial information to the available literature regarding cardiovascular aspects of JAK inhibitors in RA.

Mechanisms of Vascular Inflammation and Potential Therapeutic Targets: A Position Paper From the ESH Working Group on Small Arteries.

Inflammatory responses in small vessels play an important role in the development of cardiovascular diseases, including hypertension, stroke, and small vessel disease. This involves various complex molecular processes including oxidative stress, inflammasome activation, immune-mediated responses, and protein misfolding, which together contribute to microvascular damage. In addition, epigenetic factors, including DNA methylation, histone modifications, and microRNAs influence vascular inflammation and injury. These phenomena may be acquired during the aging process or due to environmental factors. Activation of proinflammatory signaling pathways and molecular events induce low-grade and chronic inflammation with consequent cardiovascular damage. Identifying mechanism-specific targets might provide opportunities in the development of novel therapeutic approaches. Monoclonal antibodies targeting inflammatory cytokines and epigenetic drugs, show promise in reducing microvascular inflammation and associated cardiovascular diseases. In this article, we provide a comprehensive discussion of the complex mechanisms underlying microvascular inflammation and offer insights into innovative therapeutic strategies that may ameliorate vascular injury in cardiovascular disease.

Transitions of blood immune endotypes and improved outcome by anakinra in COVID-19 pneumonia: an analysis of the SAVE-MORE randomized controlled trial.

BACKGROUND: Endotype classification may guide immunomodulatory management of patients with bacterial and viral sepsis. We aimed to identify immune endotypes and transitions associated with response to anakinra (human interleukin 1 receptor antagonist) in participants in the SAVE-MORE trial. METHODS: Adult patients hospitalized with radiological findings of PCR-confirmed severe pneumonia caused by SARS-CoV-2 and plasma-soluble urokinase plasminogen activator receptor levels of ≥ 6 ng/ml in the SAVE-MORE trial (NCT04680949) were characterized at baseline and days 4 and 7 of treatment using a previously defined 33-messenger RNA classifier to assign an immunological endotype in blood. Endpoints were changes in endotypes and progression to severe respiratory failure (SRF) associated with anakinra treatment. RESULTS: At baseline, 23.2% of 393 patients were designated as inflammopathic, 41.1% as adaptive, and 35.7% as coagulopathic. Only 23.9% were designated as the same endotype at days 4 and 7 compared to baseline, while all other patients transitioned between endotypes. Anakinra-treated patients were more likely to remain in the adaptive endotype during 7-day treatment (24.4% vs. 9.9%; p < 0.001). Anakinra also protected patients with coagulopathic endotype at day 7 against SRF compared to placebo (27.8% vs. 55.9%; p = 0.013). CONCLUSION: We identify an association between endotypes defined using blood transcriptome and anakinra therapy for COVID-19 pneumonia, with anakinra-treated patients shifting toward endotypes associated with a better outcome, mainly the adaptive endotype. Trial registration ClinicalTrials.gov, NCT04680949, December 23, 2020.

Progression to Insulin Therapy in Patients With Type 2 Diabetes According to Cardiorespiratory Fitness, Body Mass Index, and Statin Therapy.

OBJECTIVE: To evaluate the association between statin therapy, cardiorespiratory fitness (CRF), body mass index (BMI), and progression to insulin therapy in type 2 diabetes mellitus (T2DM). METHODS: Participants were patients with T2DM (mean age, 62.7±8.4 years; men, 178,992; women, 8360) not treated with insulin, with no evidence of uncontrolled cardiovascular disease, who completed an exercise treadmill test between October 1, 1999, and September 3, 2020. Of these, 158,578 were treated with statins and 28,774 were not. We established 5 age-specific CRF categories according to peak metabolic equivalents of task achieved during an exercise treadmill test. RESULTS: During a median follow-up period of 9.0 years, 51,182 patients progressed to insulin therapy with an average annual incidence rate of 28.4 events/1000 person-years. The adjusted progression rate was 27% higher in statin-treated patients (hazard ratio [HR], 1.27; 95% CI, 1.24 to 1.31), related directly to BMI and inversely related to CRF. A progressively higher rate was noted in statin-treated vs non-statin-treated patients within all BMI categories, ranging from 23% for normal weight to 90% for those with BMI of 35 kg/m2 and higher. The statin-CRF interaction revealed 43% higher rate in the least-fit statin-treated patients (HR, 1.43; 95% CI, 1.35 to 1.51) and a progressive decline with increased CRF to 30% lower risk in highly fit statin-treated patients (HR, 0.70; 95% CI, 0.66 to 0.75). CONCLUSION: In patients with T2DM, the statin-related progression to insulin therapy was associated with relatively low CRF and high BMI levels. The progression rate was mitigated by increased CRF regardless of BMI. Clinicians should foster regular exercise for patients with T2DM to enhance CRF and to lessen the rate of progression to insulin therapy.

European Society of Hypertension - general practitioners' program hypertension management: focus on general practice.

The prevalence of hypertension is rising, and the majority of patients are managed by General Physicians (GPs).GPs workload influences their capacity to follow and implement hypertension guidelines adequately.The time needed to treat (TNT) each patient at the GP level should be taken into consideration in hypertension practice guidelines.

The Hypertension Excellence Centre programme of the European Society of Hypertension - current status, activities and reshaping for the future.

PURPOSE: To describe the history of the Excellence Centre (EC) programme of the European Society of Hypertension (ESH) since the beginning in 2006, its achievements, and its future developments. MATERIALS AND METHODS: We list the number of ECs per country, the research projects performed so far, and the organisational steps needed to reshape the EC programme for the future. RESULTS: In August 2023, the ESH EC programme includes 118 registered ECs in 21 European and 7 non-European countries. Updates about the formal steps for application, re-application, transfer of EC and retirement of EC heads are given. CONCLUSIONS: The EC programme of the ESH has been a success from the beginning. Further refinements will make it fit for the next decades.

From an Empty, to an Almost Full, and Eventually to a Never Full Glass: The Evolving Challenges of Medical Education.

It has traditionally been considered that the larger the amount of knowledge, the greater the competency of a physician. However, the vertiginously fast accumulation of novel knowledge in modern medicine raises the risk that students and residents get lost in the chaos of information to which they are exposed. Thus, it becomes evident that redefining the model of medical education (and possibly rethinking what a "good" doctor means) becomes inevitable. Current challenges in medical training include early engagement of medical students in research activities and evidence-based medicine procedures, as well as adoption of new technologies, such as artificial intelligence. Gradually, the paradigm of the competent physician will transform from the "one who knows well" to "one who knows well where to search for knowledge." Given that person-centeredness remains an essential goal of medical education, supervision and assistance by academic staff are needed to ensure that the new training model has a positive impact on person-centered and doctor-patient relationships.

The Current Place of DPP4 Inhibitors in the Evolving Landscape of Type 2 Diabetes Management: Is It Time to Bid Adieu?

During the last decade, the landscape of type 2 diabetes (T2D) management has been completely transformed, moving from a glucose-centric perspective to a holistic approach that also takes into account weight control and organ protection. Dipeptidyl peptidase-4 inhibitors (DPP4i) are oral agents that have been used for the treatment of T2D for almost 20 years. Although they present an excellent safety profile, including the risk of hypoglycemia, they lack the spectacular cardiorenal benefits and weight-loss effects of the newer antidiabetic agents. This poses the question of whether they still deserve a place in the arsenal of drugs against T2D. In this article, we use a hypothetical case scenario to illustrate possible patient profiles where DPP4i could prove useful in the clinical setting. We discuss the advantages and disadvantages of the category, focusing on glycemic control, weight management, and cardiorenal protection, which are the pillars of modern T2D management, also considering its safety profile and cost-effectiveness. We conclude that in most cases, DPP4i present a more favorable risk-benefit ratio compared to sulfonylureas, which are still widely prescribed throughout the world. We also suggest that future research should clarify the reasons behind the contradictory findings between human and animal studies on cardiorenal effects of the class and identify subgroups of patients who would derive most benefit with DPP4i treatment.

Peripheral nailfold capillary microscopic abnormalities in rheumatoid arthritis are associated with arterial stiffness: Results from a cross-sectional study.

Vascular injury eventually resulting in the establishment of cardiovascular disease is a serious complication in rheumatoid arthritis (RA). Nailfold videocapillaroscopy (NVC) is a non-invasive imaging modality that enables the quantitative and qualitative assessment of the peripheral microvasculature. Nevertheless, capillaroscopic patterns remain inadequately defined in RA, especially regarding their clinical significance as potential markers of systemic vascular impairment. Consecutive RA patients underwent NVC using a standardized protocol, to assess the following parameters: capillary density, avascular areas, capillary dimensions, microhemorrhages, subpapillary venous plexus, and presence of ramified, bushy, crossed and tortuous capillaries. Carotid-femoral pulse wave velocity (PWV) and pulse pressure were measured as well-acknowledged markers of large artery stiffening. The vast majority of our cohort (n = 44) presented a combination of non-specific and abnormal capillaroscopic parameters. Capillary ramification was associated with both PWV and pulse pressure, even after adjustment for cardiovascular risk factors and systemic inflammation. Our study highlights the high prevalence of a wide range of capillaroscopic deviations from the normal patterns in RA. Furthermore, it provides for the first time evidence of an association between structural disorders of the microcirculation and markers of macrovascular dysfunction, suggesting that NVC might have a role as an index of generalised vascular impairment in RA.

The Impact of Metabolic Syndrome Components on Erectile Function in Patients with Type 2 Diabetes.

Erectile dysfunction is commonly encountered in diabetic patients and in patients with metabolic syndrome; however, only a few studies have assessed patients with metabolic syndrome and type 2 diabetes mellitus (T2DM) regarding their sexual function. The purpose of this study is to examine the effect of metabolic syndrome and its components on the erectile function of T2DM patients. A cross-sectional study including T2DM patients was conducted from November 2018 until November 2020. Participants were evaluated for the presence of metabolic syndrome and their sexual function was assessed using the International Index of Erectile Function (IIEF) questionnaire. A total of 45 consecutive male patients participated in this study. Metabolic syndrome was diagnosed in 84.4% and erectile dysfunction (ED) in 86.7% of them. Metabolic syndrome was not associated with ED or ED severity. Among metabolic syndrome components, only high-density lipoprotein cholesterol (HDL) was associated with ED [x2 (1, n = 45) = 3.894, p = 0.048; OR = 5.5 (95% CI: 0.890-33.99)] and with the IIEF erectile function scores (median 23 vs. 18, U = 75, p = 0.012). Multiple regression analyses showed that HDL was non-significantly associated with the IIEF erectile function scores. In conclusion, among T2DM patients HDL is associated with ED.

The Associations between Kidney Function and Sexual Dysfunction among Males and Females with Type 2 Diabetes Mellitus.

Background and Objectives: Diabetic kidney disease (DKD), expressed either as albuminuria, low estimated glomerular filtration rate (eGFR) or both, and sexual dysfunction (SD), are common complications among type 2 diabetes mellitus (T2DM) patients. This study aims to assess whether an association exists between DKD and SD, erectile dysfunction (ED) or female sexual dysfunction (FSD) in a T2DM population. Materials and Methods: A cross-sectional study was designed and conducted among T2DM patients. The presence of SD was assessed using the International Index of Erectile Function and the Female Sexual Function Index questionnaires for males and females, respectively, and patients were evaluated for DKD. Results: Overall, 80 patients, 50 males and 30 females, agreed to participate. Sexual dysfunction was present in 80% of the study population. Among the participants, 45% had DKD, 38.5% had albuminuria and/or proteinuria and 24.1% had an eGFR below 60 mL/min/1.73 m2. The eGFR was associated with SD, ED and FSD. Moreover, SD and ED were proven as significant determinants for lower eGFR values in multiple linear regression analyses. DKD was associated with lower lubrication scores and eGFR was associated with lower desire, arousal, lubrication and total scores; however, the multivariate linear regression analyses showed no significant associations between them. Older age resulted in significantly lower arousal, lubrication, orgasm and total FSFI scores. Conclusions: SD is commonly encountered in older T2DM patients and DKD affects almost half of them. The eGFR has been significantly associated with SD, ED and FSD, while SD and ED were proven to be significant determinants for the eGFR levels.

Cerebral oxygenation during exercise deteriorates with advancing chronic kidney disease.

BACKGROUND: Cognitive impairment and exercise intolerance are common in chronic kidney disease (CKD). Cerebral perfusion and oxygenation play a major role in both cognitive function and exercise execution. This study aimed to examine cerebral oxygenation during a mild physical stress in patients at different CKD stages and controls without CKD. METHODS: Ninety participants (18 per CKD stage 2, 3a, 3b and 4 and 18 controls) underwent a 3-min intermittent handgrip exercise at 35% of their maximal voluntary contraction. During exercise, cerebral oxygenation [oxyhaemoglobin (O2Hb), deoxyhaemoglobin (HHb) and total haemoglobin (tHb)] was assessed by near-infrared spectroscopy. Indices of microvascular (muscle hyperaemic response) and macrovascular function (carotid intima-media thickness and pulse wave velocity (PWV)) and cognitive and physical activity status were also evaluated. RESULTS: No differences in age, sex and body mass index were detected among groups. The mini-mental state examination score was significantly reduced with advancing CKD stages (controls: 29.2 ± 1.2, stage 2: 28.7 ± 1.0, stage 3a: 27.8 ± 1.9, stage 3b: 28.0 ± 1.8, stage 4: 27.6 ± 1.5; P = .019). Similar trends were observed for physical activity levels and handgrip strength. The average response in cerebral oxygenation (O2Hb) during exercise was lower with advancing CKD stages (controls: 2.50 ± 1.54, stage 2: 1.30 ± 1.05, stage 3a: 1.24 ± 0.93, stage 3b: 1.11 ± 0.89, stage 4: 0.97 ± 0.80 µmol/l; P < .001). The average tHb response (index of regional blood volume) showed a similar decreasing trend (P = .003); no differences in HHb among groups were detected. In univariate linear analysis, older age, lower estimated glomerular filtration rate (eGFR), Hb, microvascular hyperaemic response and increased PWV were associated with poor O2Hb response during exercise. In the multiple model, eGFR was the only parameter independently associated with the O2Hb response. CONCLUSIONS: Brain activation during a mild physical task appears to decrease with advancing CKD as suggested by the smaller increase in cerebral oxygenation. This may contribute to impaired cognitive function and reduced exercise tolerance with advancing CKD.

GLP-1 Receptor Agonists in Obese Patients with Inflammatory Bowel Disease: from Molecular Mechanisms to Clinical Considerations and Practical Recommendations for Safe and Effective Use.

PURPOSE OF REVIEW: To discuss current literature and provide practical recommendations for the safe and effective use of glucagon-like peptide 1 receptor agonists (GLP-1 RA) in people with inflammatory bowel disease (IBD) and type 2 diabetes (T2D) and/or obesity. The molecular mechanisms that justify the potential benefits of GLP-1 RA in IBD and the links between IBD, obesity, and cardiovascular disease are also discussed. RECENT FINDINGS: Preliminary data suggest that GLP-1 RA can modulate crucial pathways in the pathogenesis of IBD, such as chronic inflammation circuits, intestinal tight junctions, and gut microbiome dysbiosis, setting the stage for human trials to investigate the role of these agents in the treatment of IBD among people with or without diabetes and obesity. However, gastrointestinal side effects related to GLP-1 RA need appropriate clinical management to mitigate risks and maximize the benefits of therapy in people with IBD. GLP-1 RA originally emerged as drugs for the treatment of hyperglycemia and are currently licensed for the management of T2D and/or overweight/obesity. However, their wealth of pleiotropic actions soon raised expectations that they might confer benefits on non-metabolic disorders. Future studies are expected to clarify whether GLP-1 RA deserve an adjunct place in the arsenal of drugs against IBD.

Changes in Cardiorespiratory Fitness and Survival in Patients With or Without Cardiovascular Disease.

BACKGROUND: The association between cardiorespiratory fitness (CRF) and mortality risk is based mostly on 1 CRF assessment. The impact of CRF change on mortality risk is not well-defined. OBJECTIVES: This study sought to evaluate changes in CRF and all-cause mortality. METHODS: We assessed 93,060 participants aged 30-95 years (mean 61.3 ± 9.8 years). All completed 2 symptom-limited exercise treadmill tests, 1 or more years apart (mean 5.8 ± 3.7 years) with no evidence of overt cardiovascular disease. Participants were assigned to age-specific fitness quartiles based on peak METS achieved on the baseline exercise treadmill test. Additionally, each CRF quartile was stratified based on CRF changes (increase, decrease, no change) observed on the final exercise treadmill test. Multivariable Cox models were used to estimate HRs and 95% CIs for all-cause mortality. RESULTS: During a median follow-up of 6.3 years (IQR: 3.7-9.9 years), 18,302 participants died with an average yearly mortality rate of 27.6 events per 1,000 person-years. In general, changes in CRF ≥1.0 MET were associated with inverse and proportionate changes in mortality risk regardless of baseline CRF status. For example, a decline in CRF of >2.0 METS was associated with a 74% increase in risk (HR: 1.74; 95% CI: 1.59-1.91) for low-fit individuals with CVD, and 69% increase (HR: 1.69; 95% CI: 1.45-1.96) for those without CVD. CONCLUSIONS: Changes in CRF reflected inverse and proportional changes in mortality risk for those with and without CVD. The impact of relatively small CRF changes on mortality risk has considerable clinical and public health significance.

Iron therapy and severe arrhythmias in HFrEF: rationale, study design, and baseline results of the RESAFE-HF trial.

AIMS: The Iron Intravenous Therapy in Reducing the burden of Severe Arrhythmias in HFrEF (RESAFE-HF) registry study aims to provide real-word evidence on the impact of intravenous ferric carboxymaltose (FCM) on the arrhythmic burden of patients with heart failure with reduced ejection fraction (HFrEF), iron deficiency (ID), and implanted cardiac implantable electronic devices (CIEDs). METHODS AND RESULTS: The RESAFE-HF (NCT04974021) study was designed as a prospective, single-centre, and open-label registry study with baseline, 3, 6, and 12 month visits. Adult patients with HFrEF and CIEDs scheduled to receive IV FCM as treatment for ID as part of clinical practice were eligible to participate. The primary endpoint is the composite iron-related endpoint of haemoglobin ≥ 12 g/dL, ferritin ≥ 50 ng/L, and transferrin saturation > 20%. Secondary endpoints include unplanned HF-related hospitalizations, ventricular tachyarrhythmias detected by CIEDs and Holter monitors, echocardiographic markers, functional status (VO2 max and 6 min walk test), blood biomarkers, and quality of life. In total, 106 patients with a median age of 72 years (14.4) were included. The majority were male (84.9%), whereas 92.5% of patients were categorized to New York Heart Association II/III. Patients' arrhythmic burden prior to FCM administration was significant-19 patients (17.9%) received appropriate CIED therapy for termination of ventricular tachyarrhythmia in the preceding 12 months, and 75.5% of patients have frequent, repetitive multiform premature ventricular contractions. CONCLUSIONS: The RESAFE-HF trial is expected to provide evidence on the effect of treating ID with FCM in HFrEF based on real-world data. Special focus will be given on the arrhythmic burden post-FCM administration.