Towards the Fifth Pillar for the Treatment of Heart Failure with Reduced Ejection Fraction: Vericiguat in Older and Complex Patients.

Heart failure with reduced ejection fraction (HFrEF) represents an emerging epidemic, particularly affecting frail, older, and multimorbid patients. Current therapy for the management of HFrEF includes four different classes of disease-modifying drugs, commonly referred to as 'four pillars', which target the neurohormonal system that is overactivated in HF and contributes to its progression. These classes of drugs include ß-blockers, inhibitors of the renin-angiotensin-aldosterone system, mineralocorticoid receptor antagonists, and sodium-glucose co-transporter-2 (SGLT2) inhibitors. Unfortunately, these agents cannot be administered as frequently as needed to older patients because of poor tolerability and comorbidities. In addition, although these drugs have dramatically increased the survival expectations of patients with HF, their residual risk of rehospitalization and death at 5 years remains considerable. Vericiguat, a soluble guanylate cyclase (sGC) stimulator, was reported to exert beneficial effects in patients with worsening HF, including older subjects, reducing the rate of both hospitalizations and deaths, with limited adverse effects and drug interaction. In this narrative review, we present the current state of art on vericiguat, with a particular focus on elderly and frail patients.

NOX2 as a Biomarker of Academic Performance: Evidence from University Students during Examination.

BACKGROUND: Cortisol levels, oxidative stress, and lower cerebral performance seem to be closely related. This study aimed to evaluate the question of whether exam stress affected oxidative stress and endothelial function parameters in the salivary samples of students. METHODS: A total of 114 healthy students were recruited. All students were subjected to a 21-item DASS questionnaire to assess perceived stress. Cortisol levels, biomarkers of oxidative stress, and endothelial function were evaluated at T0, during the semester, and T1, in the morning before the exam, in saliva samples. In vitro, HUVECs were stimulated with cortisol, and oxidative stress and endothelial function parameters were evaluated. RESULTS: At T1, cortisol levels were significantly increased compared with the levels during the semester. Moreover, exam results correlated inversely with the DASS score at T1. In addition, NOX2, H2O2 and endothelin-1 significantly increased, while NO bioavailability decreased. In vitro, HUVECs treatment with human cortisol determined the increase of oxidative stress and the decrease of endothelial function, in association with impaired eNOS phosphorylation. CONCLUSION: NOX2-mediated oxidative stress is a mechanism that could mediate cortisol-induced transient endothelial dysfunction during academic examination. Therefore, strategies to monitor or modulate oxidative stress could help students to reduce the impact of examination-related stress.

The PAX LC Trial: A Decentralized, Phase 2, Randomized, Double-Blind Study of Nirmatrelvir/Ritonavir Compared with Placebo/Ritonavir for Long COVID.

BACKGROUND: Individuals with long COVID lack evidence-based treatments and have difficulty participating in traditional site-based trials. Our digital, decentralized trial investigates the efficacy and safety of nirmatrelvir/ritonavir, targeting viral persistence as a potential cause of long COVID. METHODS: The PAX LC trial (NCT05668091) is a Phase 2, 1:1 randomized, double-blind, superiority, placebo-controlled trial in 100 community-dwelling, highly symptomatic adult participants with long COVID residing in the 48 contiguous US states to determine the efficacy, safety, and tolerability of 15 days of nirmatrelvir/ritonavir compared with placebo/ritonavir. Participants are recruited via patient groups, cultural ambassadors, and social media platforms. Medical records are reviewed through a platform facilitating participant-mediated data acquisition from electronic health records nationwide. During the drug treatment, participants complete daily digital diaries using a web-based application. Blood draws for eligibility and safety assessments are conducted at or near participants' homes. The study drug is shipped directly to participants' homes. The primary endpoint is the PROMIS-29 Physical Health Summary Score difference between baseline and Day 28, evaluated by a mixed model repeated measure analysis. Secondary endpoints include PROMIS-29 (Mental Health Summary Score and all items), Modified GSQ-30 with supplemental symptoms questionnaire, COVID Core Outcome Measures for Recovery, EQ-5D-5L (Utility Score and all items), PGIS 1 and 2, PGIC 1 and 2, and healthcare utilization. The trial incorporates immunophenotyping to identify long COVID biomarkers and treatment responders. CONCLUSION: The PAX LC trial uses a novel decentralized design and a participant-centric approach to test a 15-day regimen of nirmatrelvir/ritonavir for long COVID.

Effects of two-month treatment with a mixture of natural activators of autophagy on oxidative stress and arterial stiffness in patients with essential hypertension: A pilot study.

BACKGROUND AND AIMS: Trehalose, spermidine, nicotinamide, and polyphenols are natural substances that exert pro-autophagic and antioxidant properties. Their role in blood pressure (BP) regulation and preservation of vascular function in essential hypertension is unknown. The aim of this study was to evaluate the effect of a mixture of these agents on BP level, markers of oxidative stress, autophagy, endothelial function, and vascular stiffness in outpatients with grade 1 uncomplicated essential hypertension. METHODS AND RESULTS: A single-centre, open-label, case-control, pilot study was conducted in adult outpatients (aged ≥18 years) receiving or not the mixture for two months along with the standard therapies. Both at baseline and at the end of the treatment the following clinical parameters were evaluated: brachial seated office BP level, central aortic pressure, pulse wave velocity, augmentation index (AI@75). Both at baseline and at the end of the treatment, a blood sample was drawn for the measurement of: H2O2, HBA%, levels of sNOX2-dp, Atg 5, P62, endothelin 1, and NO bioavailability. The mixture of nutraceuticals did not influence BP levels. Patients receiving the mixture showed a significant decrease of oxidative stress, stimulation of autophagy, increased NO bioavailability and no increase of the AI@75, in contrast to what observed in hypertensive patients not receiving the mixture. CONCLUSIONS: The supplementation of the trehalose, spermidine, nicotinamide, and polyphenols mixture counteracted hypertension-related arterial stiffness through mechanisms likely dependent on oxidative stress downregulation and autophagy stimulation. These natural activators of autophagy may represent favourable adjuvants for prevention of the hypertensive cardiovascular damage.

Short-Term Atrioventricular Dysfunction Recovery after Post-TAVI Pacemaker Implantation.

Permanent pacemaker implantation (PPI) represents a frequent complication after transcatheter aortic valve implantation (TAVI) due to atrio-ventricular (AV) node injury. Predictors of early AV function recovery were investigated. We analyzed 50 consecutive patients (82 ± 6 years, 58% males, EuroSCORE: 7.8 ± 3.3%, STS mortality score: 5 ± 2.8%). Pacemaker interrogations within 4−6 weeks from PPI were performed to collect data on AV conduction. The most common indication of PPI was persistent third-degree (44%)/high-degree (20%) AV block/atrial fibrillation (AF) with slow ventricular conduction (16%) after TAVI. At follow-up, 13 patients (26%) recovered AV conduction (i.e., sinus rhythm with stable 1:1 AV conduction/AF with a mean ventricular response >50 bpm, associated with a long-term ventricular pacing percentage < 5%). At multivariate analysis, complete atrio-ventricular block independently predicted pacemaker dependency at follow-up (p = 0.019). Patients with persistent AV dysfunction showed a significant AV conduction time prolongation after TAVI (PR interval from 207 ± 50 to 230 ± 51, p = 0.02; QRS interval from 124 ± 23 to 147 ± 16, p < 0.01) compared to patients with recovery, in whom AV conduction parameters remained unchanged. Several patients receiving PPI after TAVI have recovery of AV conduction within a few weeks. Longer observation periods prior to PPI might be justified, and algorithms to minimize ventricular pacing should be utilized whenever possible.

Advances and Challenges in Biomarkers Use for Coronary Microvascular Dysfunction: From Bench to Clinical Practice.

Coronary microvascular dysfunction (CMD) is related to a broad variety of clinical scenarios in which cardiac microvasculature is morphologically and functionally affected, and it is associated with impaired responses to vasoactive stimuli. Although the prevalence of CMD involves about half of all patients with chronic coronary syndromes and more than 20% of those with acute coronary syndrome, the diagnosis of CMD is often missed, leading to the underestimation of its clinical importance. The established and validated techniques for the measurement of coronary microvascular function are invasive and expensive. An ideal method to assess endothelial dysfunction should be accurate, non-invasive, cost-effective and accessible. There are varieties of biomarkers available, potentially involved in microvascular disease, but none have been extensively validated in this heterogeneous clinical population. The investigation of potential biomarkers linked to microvascular dysfunction might improve the assessment of the diagnosis, risk stratification, disease progression and therapy response. This review article offers an update about traditional and novel potential biomarkers linked to CMD.

Prevalence and characteristics of myocardial injury during COVID-19 pandemic: A new role for high-sensitive troponin.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a pandemic disease that is causing a public health emergency. Characteristics and clinical significance of myocardial injury remain unclear. METHODS: This retrospective single-center study analyzed 189 patients who received a COVID-19 diagnosis out of all 758 subjects with a high sensitive troponin I (Hs-TnI) measurement within the first 24 h of admission at the Policlinico A.Gemelli (Rome, Italy) between February 20th 2020 to April 09th 2020. RESULTS: The prevalence of myocardial injury in our COVID-19 population is of 16%. The patients with cardiac injury were older, had a greater number of cardiovascular comorbidities and higher values of acute phase and inflammatory markers and leucocytes. They required more frequently hospitalization in Intensive Care Unit (10 [32.3%] vs 18 [11.4%]; p = .003) and the mortality rate was significantly higher (17 [54.8%] vs. 15 [9.5%], p < .001). Among patients in ICU, the subjects with myocardial injury showed an increase need of endotracheal intubation (8 out of 9 [88%] vs 7 out of 19[37%], p = .042). Multivariate analyses showed that hs-TnI can significantly predict the degree of COVID-19 disease, the intubation need and in-hospital mortality. CONCLUSIONS: In this study we demonstrate that hs-Tn can significantly predict disease severity, intubation need and in-hospital death. Therefore, it may be reasonable to use Hs-Tn as a clinical tool in COVID-19 patients in order to triage them into different risk groups and can play a pivotal role in the detection of subjects at high risk of cardiac impairment during both the early and recovery stage.

[Cardiac contractility modulation: a treatment option for patients with refractory heart failure]. / La modulazione della contrattilità cardiaca: un'opzione terapeutica per il paziente con insufficienza cardiaca refrattaria.

Heart failure is the cardiovascular epidemic of the 21st century, with poor prognosis and quality of life despite optimized medical treatment. In the past two decades, only two new drugs have been added to therapeutic strategies for patients with symptomatic heart failure and even less progresses have been made on devices, with the implantable defibrillator indicated for patients with ejection fraction ≤35% and cardiac resynchronization therapy for those with QRS >130 ms and evidence of left bundle branch block. Nevertheless, only a third of patients meet these criteria and a high percentage of patients are non-responders in terms of improving symptoms. Nowadays, in patients with symptomatic heart failure with ejection fraction between 25% and 45% and QRS <130 ms, not eligible for cardiac resynchronization therapy, cardiac contractility modulation represents a concrete treatment option, having proved to be safe and effective in reducing hospitalizations for heart failure and improving symptoms, functional capacity and quality of life.The aim of this review is therefore to summarize the pathophysiological mechanisms, the current indications and the recent developments regarding the new applications of cardiac contractility modulation for patients with chronic heart failure.

Ventricular arrhythmias in Takotsubo Syndrome: incidence, predictors and clinical outcomes.

AIMS: To investigate predictors of the occurrence of subacute ventricular arrhythmias (VAs), defined as any VAs presenting after 48 h from admission in patients with Takotsubo Syndrome (TTS), and to evaluate the related in-hospital mortality. METHODS: This is a retrospective single-center study enrolling patients admitted between 2012 and 2017 with TTS according to International Takotsubo diagnostic criteria. Data collection included ECG on admission and at 48 h, telemetry monitoring and transthoracic echocardiogram. RESULTS: We enrolled 93 patients; during in-hospital stay (mean 14 ±â€Š16 days) subacute VAs occurred in 25% of patients (VAs group). Life-threatening VAs occurred in 6% of patients (3 sustained ventricular tachycardia, 1 torsade de pointes, 1 ventricular fibrillation) and not life-threatening VAs in 19% (6 non-sustained ventricular tachycardia and 12 premature ventricular contractions > 2000 in 24 h). Mortality was higher in the VAs than in the non-VAs group (P = 0.03), without differences in terms of life-threatening and not life-threatening subacute VAs (P = 0.65) and VAs on admission (P = 0.25). Logistic regression identified the following independent predictors of subacute VAs occurrence: VAs on admission {odds ratio [OR] 22.5 (3.9-131.8), P = 0.001]}, New York Heart Association (NYHA) class III-IV on admission [OR 6.7 (1.3- 34.0), P = 0.021] and QTc at 48 h [OR 1.01 (1.00-1.03), P = 0.046]. CONCLUSION: TTS patients with VAs and NYHA class III-IV on admission and higher QTc at 48 h are at increased risk of subacute VAs occurrence, associated with higher in-hospital mortality. Awareness of this potential complication is critical for proper patients management.

Cardiac contractility modulation for patient with refractory heart failure: an updated evidence-based review.

Heart failure is the cardiovascular epidemic of the twenty-first century, with poor prognosis and quality of life despite optimized medical treatment. Despite over the last decade significant improvements, with a major impact on morbidity and mortality, have been made in therapy for heart failure with reduced ejection fraction, little progress was made in the development of devices, with the implantable defibrillator indicated for patients with left ventricle ejection fraction ≤ 35% and cardiac resynchronization therapy for those with QRS ≥ 130 ms and evidence of left bundle branch block. Nevertheless, only a third of patients meet these criteria and a high percentage of patients are non-responders in terms of improving symptoms. Nowadays, in patients with symptomatic heart failure with ejection fraction between 25% and 45% and QRS < 130 ms, not eligible for cardiac resynchronization, the cardiac contractility modulation (CCM) represents a concrete therapeutic option, having proved to be safe and effective in reducing hospitalizations for heart failure and improving symptoms, functional capacity, and quality of life. The aim of this review is therefore to summarize the pathophysiological mechanisms, the current indications, and the recent developments regarding the new applications of the CCM for patients with chronic heart failure.

High-sensitivity cardiac troponin assays and acute coronary syndrome: a matter of sex?

: Advances in technology have led to an improvement in the ability to detect and quantify acute cardiomyocyte injury with the measurement of high-sensitivity cardiac troponin as compared with conventional assays. The upper reference limit for the high-sensitivity cardiac troponin assays is defined as the 99th percentile cutoff value in a healthy reference population. Since sex-related threshold levels of high-sensitivity cardiac troponin assays have been proposed, this review will focus on the diagnostic and prognostic implications of adopting sex-specific threshold troponin values in patients with a suspected acute coronary syndrome.