Inflammaging: The Next Challenge-Exploring the Role of Gut Microbiota, Environmental Factors, and Sex Differences.

The term 'inflammaging' has been coined to describe the chronic state of inflammation derived from ongoing cycles of tissue damage and the subsequent immune responses. This inflammatory status contributes to the decline of organs and physiological functions, accelerates the aging process, and increases the risk of age-related illnesses and death. During aging, the gut microbiota (GM) undergoes significant changes, including a decreased diversity of species, a decline in beneficial bacteria, and a rise in proinflammatory ones, resulting in persistent low-grade inflammation. Moreover, environmental factors, such as diet and medications, contribute to age-related changes in GM and immune function, preventing or promoting inflammaging. This narrative review aims to clarify the underlying mechanisms of inflammaging and to specifically investigate the influence of GM and several environmental factors on these mechanisms, while also exploring potential differences related to sex. Moreover, lifestyle and pharmacological interventions will be suggested to promote healthy aging.

Complete vs Culprit-Only Revascularization in Older Patients With Myocardial Infarction and High Bleeding Risk: A Randomized Clinical Trial.

Importance: Patients with high bleeding risk (HBR) have a poor prognosis, and it is not known if they may benefit from complete revascularization after myocardial infarction (MI). Objective: To investigate the benefit of physiology-guided complete revascularization vs a culprit-only strategy in patients with HBR, MI, and multivessel disease. Design, Setting, and Participants: This was a prespecified analysis of the Functional Assessment in Elderly MI Patients With Multivessel Disease (FIRE) randomized clinical trial data. FIRE was an investigator-initiated, open-label, multicenter trial. Patients 75 years or older with MI and multivessel disease were enrolled at 34 European centers from July 2019 through October 2021. Physiology treatment was performed either by angiography- or wire-based assessment. Patients were divided into HBR or non-HBR categories in accordance with the Academic Research Consortium HBR document. Interventions: Patients were randomized to either physiology-guided complete revascularization or culprit-only strategy. Main Outcomes and Measures: The primary outcome comprised a composite of death, MI, stroke, or revascularization at 1 year. Secondary outcomes included a composite of cardiovascular death or MI and Bleeding Academic Research Consortium (BARC) types 3 to 5. Results: Among 1445 patients (mean [SD] age, 81 [5] years; 917 male [63%]), 1025 (71%) met HBR criteria. Patients with HBR were at higher risk for the primary end point (hazard ratio [HR], 2.01; 95% CI, 1.47-2.76), cardiovascular death or MI (HR, 1.89; 95% CI, 1.26-2.83), and BARC types 3 to 5 (HR, 3.28; 95% CI, 1.40-7.64). The primary end point was significantly reduced with physiology-guided complete revascularization as compared with culprit-only strategy in patients with HBR (HR, 0.73; 95% CI, 0.55-0.96). No indication of interaction was noted between revascularization strategy and HBR status for primary and secondary end points. Conclusions and Relevance: HBR status is prevalent among older patients with MI, significantly increasing the likelihood of adverse events. Physiology-guided complete revascularization emerges as an effective strategy, in comparison with culprit-only revascularization, for mitigating ischemic adverse events, including cardiovascular death and MI. Trial Registration: ClinicalTrials.gov Identifier: NCT03772743.

QFR for the Revascularization of Nonculprit Vessels in MI Patients: Insights From the FIRE Trial.

BACKGROUND: The role of quantitative flow ratio (QFR) in the treatment of nonculprit vessels of patients with myocardial infarction (MI) is a topic of ongoing discussion. OBJECTIVES: This study aimed to investigate the predictive capability of QFR for adverse events and its noninferiority compared to wire-based functional assessment in nonculprit vessels of MI patients. METHODS: The FIRE (Functional Assessment in Elderly MI Patients With Multivessel Disease) trial randomized 1,445 older MI patients to culprit-only (n = 725) or physiology-guided complete revascularization (n = 720). In the culprit-only arm, angiographic projections of nonculprit vessels were prospectively collected, centrally reviewed for QFR computation, and associated with endpoints. In the complete revascularization arm, endpoints were compared between nonculprit vessels investigated with QFR or wire-based functional assessment. The primary endpoint was the vessel-oriented composite endpoint (VOCE) at 1 year. RESULTS: QFR was measured on 903 nonculprit vessels from 685 patients in the culprit-only arm. Overall, 366 (40.5%) nonculprit vessels showed a QFR value ≤0.80, with a significantly higher incidence of VOCEs (22.1% vs 7.1%; P < 0.001). QFR ≤0.80 emerged as an independent predictor of VOCEs (HR: 2.79; 95% CI: 1.64-4.75). In the complete arm, QFR was used in 320 (35.2%) nonculprit vessels to guide revascularization. When compared with propensity-matched nonculprit vessels in which treatment was guided by wire-based functional assessment, no significant difference was observed (HR: 0.57; 95% CI: 0.28-1.15) in VOCEs. CONCLUSIONS: This prespecified subanalysis of the FIRE trial provides evidence supporting the safety and efficacy of QFR-guided interventions for the treatment of nonculprit vessels in MI patients. (Functional Assessment in Elderly MI Patients With Multivessel Disease [FIRE]; NCT03772743).

Gut-Brain Axis: Focus on Sex Differences in Neuroinflammation.

In recent years, there has been a growing interest in the concept of the "gut-brain axis". In addition to well-studied diseases associated with an imbalance in gut microbiota, such as cancer, chronic inflammation, and cardiovascular diseases, research is now exploring the potential role of gut microbial dysbiosis in the onset and development of brain-related diseases. When the function of the intestinal barrier is altered by dysbiosis, the aberrant immune system response interacts with the nervous system, leading to a state of "neuroinflammation". The gut microbiota-brain axis is mediated by inflammatory and immunological mechanisms, neurotransmitters, and neuroendocrine pathways. This narrative review aims to illustrate the molecular basis of neuroinflammation and elaborate on the concept of the gut-brain axis by virtue of analyzing the various metabolites produced by the gut microbiome and how they might impact the nervous system. Additionally, the current review will highlight how sex influences these molecular mechanisms. In fact, sex hormones impact the brain-gut microbiota axis at different levels, such as the central nervous system, the enteric nervous one, and enteroendocrine cells. A deeper understanding of the gut-brain axis in human health and disease is crucial to guide diagnoses, treatments, and preventive interventions.

Impact of pre-admission physical activity on benefits of physiology-guided complete revascularization in older patients with myocardial infarction: insights from the FIRE trial.

AIMS: The present analysis from the Functional Assessment in Elderly Myocardial Infarction Patients with Multivessel Disease (FIRE) trial aims to explore the significance of pre-admission physical activity and assess whether the benefits of physiology-guided complete revascularization apply consistently to sedentary and active older patients. METHODS AND RESULTS: Patients aged 75 years or more with myocardial infarction (MI) and multivessel disease were randomized to receive physiology-guided complete revascularization or culprit-only strategy. The primary outcome was a composite of death, MI, stroke, or any revascularization within a year. Secondary endpoints included the composite of cardiovascular death or MI, as well as single components of the primary endpoint. Pre-admission physical activity was categorized into three groups: (i) absent (sedentary), (ii) light, and (iii) vigorous. Among 1445 patients, 692 (48%) were sedentary, whereas 560 (39%) and 193 (13%) performed light and vigorous physical activity, respectively. Patients engaging in light or vigorous pre-admission physical activity exhibited a reduced risk of the primary outcome compared with sedentary individuals [light hazard ratio (HR) 0.70, 95% confidence interval (CI) 0.55-0.91 and vigorous HR 0.14, 95% CI 0.07-0.91, respectively]. These trends were also observed for death, cardiovascular death, or MI. When comparing physiology-guided complete revascularization vs. culprit-only strategy, no significant interaction was observed for primary and secondary endpoints when stratified by sedentary or active status. CONCLUSION: In older patients with MI, pre-admission physical activity emerges as a robust and independent prognostic determinant. Physiology-guided complete revascularization stands out an effective strategy in reducing ischaemic adverse events, irrespective of pre-admission physical activity status. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT03772743.

The Functional Assessment in Elderly Myocardial Infarction Patients with Multivessel Disease (FIRE) trial has shown that physiology-guided complete revascularization reduces ischaemic adverse events in older patients with myocardial infarction (MI) and multivessel disease. Older patients who engage in light or vigorous physical activity before hospitalization for MI have a reduced risk of the primary composite outcome of death, MI, stroke, or ischaemia-driven revascularization. These benefits extend to all secondary cardiovascular outcomes as well. In the present subanalysis of the FIRE trial, we find that the positive prognosis associated with physiology-guided complete revascularization holds true even for patients with a sedentary lifestyle. This means that this type of revascularization can effectively reduce ischaemic adverse events in older patients with MI and multivessel disease, regardless of their physical activity levels.

Coronary Sinus Narrowing Improves Coronary Microcirculation Function in Patients With Refractory Angina: A Multicenter Prospective INROAD Study.

BACKGROUND: The underlying mechanisms responsible for the clinical benefits following coronary sinus narrowing and pressure elevation remain unclear. The present study aims to investigate whether coronary sinus narrowing improves the indexes of coronary microcirculatory function. METHODS: Patients with refractory angina who had a clinical indication for reducer implantation underwent invasive physiological assessments before and 4 months after the procedure. The primary outcome was the change in the values of the index of microcirculatory resistance. Secondary end points included changes in coronary flow reserve and the resistive resistance ratio values. Angina status was assessed with the Canadian Cardiology Society class and the Seattle Angina Questionnaire. RESULTS: Twenty-four patients with a history of obstructive coronary artery disease and prior coronary revascularization (surgical and percutaneous) treated with reducer implantation were enrolled, and 21 of them (87%) underwent repeated invasive coronary physiological assessment after 4 months. The index of microcirculatory resistance values decreased from 33.35±19.88 at baseline to 15.42±11.36 at 4-month follow-up (P<0.001; mean difference, -17.90 [95% CI, -26.16 to -9.64]). A significant (≥20% from baseline) reduction of the index of microcirculatory resistance was observed in 15 (71.4% [95% CI, 47.8%-88.7%]) patients. The number of patients with abnormal index of microcirculatory resistance (≥25) decreased from 12 (57%) to 4 (19%; P=0.016). Coronary flow reserve increased from 2.46±1.52 to 4.20±2.52 (mean difference, 1.73 [95% CI, 0.51-2.96]). Similar findings were observed for resistive resistance ratio values. Overall, 16 patients (76.1%) had an improvement of 1 Canadian Cardiology Society class. Seattle Angina Questionnaire summary score increase of around 3 points (3.01 [95% CI, 1.39-4.61]). CONCLUSIONS: Coronary sinus reduction implantation is associated with a significant improvement in the parameters of coronary microcirculatory function. These findings provide insights into the improvement of angina symptoms and may have implications for the treatment of coronary microvascular dysfunction. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05174572.

Coronary Physiology Guidance vs Conventional Angiography for Optimization of Percutaneous Coronary Intervention: The AQVA-II Trial.

BACKGROUND: The debate surrounding the efficacy of coronary physiological guidance compared with conventional angiography in achieving optimal post-percutaneous coronary intervention (PCI) fractional flow reserve (FFR) values persists. OBJECTIVES: The primary aim of this study was to demonstrate the superiority of physiology-guided PCI, using either angiography or microcatheter-derived FFR, over conventional angiography-based PCI in complex high-risk indicated procedures (CHIPs). The secondary aim was to establish the noninferiority of angiography-derived FFR guidance compared with microcatheter-derived FFR guidance. METHODS: Patients with obstructive coronary lesions and meeting CHIP criteria were randomized 2:1 to receive undergo physiology- or angiography-based PCI. Those assigned to the former were randomly allocated to angiography- or microcatheter-derived FFR guidance. CHIP criteria were long lesion (>28 mm), tandem lesions, severe calcifications, severe tortuosity, true bifurcation, in-stent restenosis, and left main stem disease. The primary outcome was invasive post-PCI FFR value. The optimal post-PCI FFR value was defined as >0.86. RESULTS: A total of 305 patients (331 study vessels) were enrolled in the study (101 undergoing conventional angiography-based PCI and 204 physiology-based PCI). Optimal post-PCI FFR values were more frequent in the physiology-based PCI group compared with the conventional angiography-based PCI group (77% vs 54%; absolute difference 23%, relative difference 30%; P < 0.0001). The occurrence of the primary outcome did not differ between the 2 physiology-based PCI subgroups, demonstrating the noninferiority of angiography- vs microcatheter-derived FFR (P < 0.01). CONCLUSIONS: In CHIP patients, procedural planning and guidance on the basis of physiology (through either angiography- or microcatheter-derived FFR) are superior to conventional angiography for achieving optimal post-PCI FFR values. (Physiology Optimized Versus Angio-Guided PCI [AQVA-II]; NCT05658952).

Functional (Re)Development of SYNTAX Score II 2020: Predictive Performance and Risk Assessment.

The present study investigates the prognostic value of the Syntax Score II 2020 corrected for flow-limiting lesions and its ability to better address treatment by benefit prediction among patients with left main or multivessel disease. We analyzed 1274 patients from the HALE-BOPP cohort and integrated the Syntax Score II 2020 with the result of the fractional flow reserve (FFR) evaluation. Absolute risk difference (ARD) between surgical and percutaneous revascularization was calculated for anatomic and functional Syntax Score II 2020 predicted mortality. The ARD allowed to stratify the population into two large categories: "coronary artery bypass graft (CABG) better" with ARD ≥ 4.5% and "CABG-percutaneous coronary intervention (PCI) equipoise" with ARD < 4.5%. The mean global anatomical Syntax Score was 15.5 ± 9.2, whereas the functional one was 9.5 ± 10 (p < 0.01). Using the anatomic Syntax Score II 2020, 881 patients had a CABG-PCI equipoise. This number increased to 1041 after considering only flow-limiting lesions by FFR (p < 0.001); therefore, 40% of CABG better patients were reclassified within the CABG-PCI equipoise category. Kaplan-Maier curves showed similar actual survival rates for patients originally with CABG-PCI equipoise and those reclassified, in both cases higher than those from CABG better patients (p < 0.01). The integration between Syntax Score II 2020 and physiology is feasible, and merging clinical, anatomic and functional data allows for better risk prediction and therapeutic guidance.