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.

Physical Activity and Cardiac Morphologic Adaptations.

Chronic and intense exercise programs lead to cardiac adaptations, followed by increased left ventricular wall thickness and cavity diameter, at times meeting the criteria for left ventricular hypertrophy (LVH), commonly referred to as "athlete's heart". Recent studies have also reported that extremely vigorous exercise practices have been associated with heightened left ventricular trabeculation extent, fulfilling noncompaction cardiomyopathy criteria, as part of exercise-induced structural adaptation. These changes are specific to the exercise type, intensity, duration, and volume and workload demands imposed on the myocardium. They are considered physiologic adaptations not associated with a negative prognosis. Conversely, hypertrophic cardiac adaptations resulting from chronic elevations in blood pressure (BP) or chronic volume overload due to valvular regurgitation, lead to compromised cardiac function, increased cardiovascular events, and even death. In younger athletes, hypertrophic cardiomyopathy (HCM) is the usual cause of non-traumatic, exercise-triggered sudden cardiac death. Thus, an extended cardiac examination should be performed, to differentiate between HCM and non-pathological exercise-related LVH or athlete's heart. The exercise-related cardiac structural and functional adaptations are normal physiologic responses designed to accommodate the increased workload imposed by exercise. Thus, we propose that such adaptations are defined as "eutrophic" hypertrophy and that LVH is reserved for pathologic cardiac adaptations. Systolic BP during daily activities may be the strongest predictor of cardiac adaptations. The metabolic demand of most daily activities is approximately 3-5 metabolic equivalents (METs) (1 MET = 3.5 mL of O 2 kg of body weight per minute). This is similar to the metabolic demand of treadmill exercise at the first stage of the Bruce protocol. Some evidence supports that an exercise systolic BP response ≥ 150 mmHg at the end of that stage is a strong predictor of left ventricular hypertrophy, as this BP reflects the hemodynamic burden of most daily physical tasks. Aerobic training of moderate intensity lowers resting and exercise systolic BP at absolute workloads, leading to a lower hemodynamic burden during daily activities, and ultimately reducing the stimulus for LVH. This mechanism explains the significant LVH regression addressed by aerobic exercise intervention clinical studies.

Exercise, Erectile Dysfunction and Co-Morbidities: "The Good, the Bad and the Ugly".

Erectile dysfunction (ED), defined as the inability to attain or maintain sufficient penile erection for sexual intercourse, is a growing health problem, which unfortunately remains underreported, underdiagnosed and undertreated. Growing evidence suggests that ED is a promising cardiovascular risk marker, as it is associated with major co-morbidities increasing cardiovascular disease burden, while it is an independent predictor of cardiovascular morbidity and mortality. The role of exercise as a non-pharmacological therapeutic intervention in ED has been widely investigated during the last two decades, both in observational studies and in randomized controlled trials, enrolling different patients' populations. In the present narrative review, we summarize relevant evidence concerning the effect of exercise on vascular ED and the pathophysiologic background, underscoring the importance of enhanced physical activity as a recommendation in all subjects with vascular ED.

Therapeutic Potential of Sodium-glucose Co-transporter-2 Inhibitors and Glucagon-like Peptide-1 Receptor Agonists for Patients with Acute Coronary Syndrome: A Review of Clinical Evidence.

Atherosclerotic Cardiovascular Disease (ASCVD) is still one of the leading causes of death globally, with Coronary Artery Disease (CAD) being the most prevalent form of ASCVD. Patients with type 2 Diabetes Mellitus (DM) experience an increased risk for ASCVD during the disease course, with CAD being the most common cause of death among affected individuals, resulting in shorter life expectancy and increased morbidity among survivors. Recently, 2 novel classes of anti-diabetic drugs, namely Sodium-Glucose co-Transporter-2 (SGLT-2) inhibitors and Glucagon-Like Peptide-1 (GLP-1) receptor agonists, have shown impressive cardio-renal benefits for patients with type 2 DM, while they might decrease cardio-renal risk even in the absence of baseline DM. However, there is no evidence to date regarding their safety and efficacy in the setting of an acute coronary syndrome (ACS) event, regardless of concomitant DM. This study aims to provide a detailed, updated presentation of currently available clinical evidence concerning the potential role of SGLT-2 inhibitors and GLP-1 receptor agonists in the setting of an ACS, and to highlight whether those drug classes could be utilized as adjuncts to standard-of-care treatment in this specific patient population, along with a presentation of the potential short- and long-term cardiovascular benefits.

Above the Clouds with Diabetes: From Pathophysiological Considerations to Practical Recommendations for Safe Flights.

Vasdeki, Dimitra, Georgios Tsamos, Kleoniki I. Athanasiadou, Vasiliki Michou, Evangelos Botsarakos, Michael Doumas, Kalliopi Kotsa, and Theocharis Koufakis. Above the clouds with diabetes: From pathophysiological considerations to practical recommendations for safe flights. High Alt Med Biol. 00:00-00, 2024. Background: The prevalence of diabetes mellitus has been following an increasing trend in the last decades, leading to a growing number of travelers with diabetes seeking pretravel advice from medical professionals. Methods: This narrative review summarizes the existing evidence on the intriguing association between diabetes and air travel, analyzes safety and certification protocols, and provides practical recommendations for the management of diabetes during flights. Results: During air travel, individuals with diabetes face challenges arising from inappropriate dietary options, restricted access to medications and healthcare services, disruption of medication dosing intervals, and exposure to hypobaric conditions in the airplane cabin. In addition, people with diabetes, especially those treated with insulin, have traditionally been considered ineligible to become professional pilots. However, this approach gradually changes and numerous countries are now implementing strict protocols to determine the eligibility of pilots with diabetes to operate flights. Conclusions: Given the increasing use of technology and new drugs in daily clinical practice, there is a need for further research in the field to shed light on existing knowledge gaps and ensure safe flights for people with diabetes.

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.

Achievement of normoglycemia with tirzepatide in type 2 diabetes mellitus: A step closer to drug-induced diabetes remission?

We sought to determine whether treatment with tirzepatide in type 2 diabetes mellitus (T2DM) patients can increase the odds for achieving normoglycemia, compatible with glycated hemoglobin levels lower than 5.7 %. We demonstrated that treatment with tirzepatide versus control increased the odds for achievement of normoglycemia by >16 times.

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.

Prevalence, awareness, and control of hypertension in Greece before and after the COVID-19 pandemic: May Measurement Month survey 2019-2022.

OBJECTIVE: The COVID-19 pandemic had an adverse impact on several cardiovascular risk factors. This study investigated the prevalence, awareness and treatment of hypertension in Greece before and after the pandemic. Data were collected in the context of the May Measurement Month (MMM) global survey initiated by the International Society of Hypertension. METHODS: Adult volunteers (age ≥ 18 years) were recruited through opportunistic screening in public areas across cities in Greece in 2019 and 2022. Medical history and triplicate sitting blood pressure (BP) measurements were taken using validated automated upper-arm cuff devices. The data were uploaded to the international MMM cloud platform. Hypertension was defined as systolic BP ≥ 140 mm Hg and/or diastolic ≥90 mm Hg and/or self-reported use of drugs for hypertension. The same threshold was used to define uncontrolled BP in treated individuals. RESULTS: Data from 12,080 adults were collected (5,727/6,353 in MMM 2019/2022; men 46/49%, p < 0.01; mean age 52.7 ± 16.6/54.8 ± 16.2, p < 0.001; smokers, 24.7/30.5, p < 0.001; diabetics 12/11.5%, p = NS; cardiovascular disease 5/5.8%, p = NS). The prevalence of hypertension was 41.6/42.6% (MMM 2019/2022, p = NS), with 21.3/27.5% of individuals with hypertension being unaware of their condition (p < 0.001), 5.6/2.4% aware untreated (p < 0.001), 24.8/22.1% treated uncontrolled (p < 0.05), and 48.3/47.8% treated controlled (p = NS). CONCLUSION: In Greece, the COVID-19 pandemic did not appear to affect the prevalence and control of hypertension; however, the rate of undiagnosed hypertension was higher after the pandemic. National strategies need to be implemented for the early detection and optimal management of hypertension in the general population in Greece.

Male and female sexual dysfunction: is hypertension an innocent bystander or a major contributor?

Sexual dysfunction represents a major quality-of-liferelated health problem, and available data indicate that essential hypertension is a risk factor for sexual dysfunction in both men and women. Male and female sexual dysfunction is more prevalent in hypertensive than normotensive individuals, and several mechanisms have been implicated in the pathogenesis of sexual dysfunction in hypertensive patients. Several factors affect the sexual function of hypertensive function, such as severity and duration of hypertension, age, and antihypertensive therapy. Older antihypertensive drugs (diuretics, ß-blockers, centrallyacting) exert negative results while never drugs have either neutral (Ca-antagonists, ACE-inhibitors) or beneficial effects (angiotensin receptor blockers). Female sexual dysfunction, although more frequent than the male one, remains largely under investigated possibly due to the lackof effective treatment. A better understanding of sexual functioning and appropriate education of doctors at medical schools and specific seminars would result in a more effective approach of sexual dysfunction by practitioners dealing with hypertensive patients.