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.

The risk of acute coronary events in microvascular disease.

The microvascular disease represents a widespread clinical entity in the general population, especially among women. The dysfunction of the microcirculation is often responsible for myocardial ischaemia and angina in the absence of significant stenosis of the epicardial district, while in other cases it can represent a contributing cause of angina even in the presence of coronary artery disease, cardiomyopathies or heart failure. The cardiovascular risk factors of people with microvascular disease are similar to those who develop epicardial atherosclerotic disease. However, the prognostic significance of microvascular disease remains a matter of debate. An element to be clarified, in fact, is whether subjects with dysfunction of the microcirculation and coronary tree without significant stenoses present an increased risk of myocardial infarction and sudden death. In recent years, several studies seem to confirm an association between microvascular disease and progression of coronary epicardial atherosclerosis. The prognosis of microvascular disease would therefore not be benign as was previously believed, but associated with an increased risk of cardiovascular events including revascularization, heart attack, and cardiac death.

Renal arteries denervation: from the treatment of resistant hypertension to the treatment of atrial fibrillation.

Renal denervation (RDN) is a therapeutic strategy for patients with uncontrolled arterial hypertension characterized by considerable fluctuations during its progression. After initial strong enthusiasm, the procedure came to an abrupt halt following the publication of the Symplicity HTN-3 study results. The results of recently published studies highlight the reduction in blood pressure values after RDN and justify the inclusion in the Guidelines of new recommendations for the use of RDN in clinical practice, in selected patients. Additionally, RDN findings are summarized in view of other potential indications such as atrial fibrillation. Six prospective, randomized studies are presented that evaluated RDN as an adjunct therapy to pulmonary vein isolation for the treatment of atrial fibrillation. In five studies, patients had uncontrolled hypertension despite therapy with three antihypertensive drugs. The analysis of these studies showed that RDN reduced the recurrence of atrial fibrillation (AF) by 57% compared to patients with pulmonary vein isolation (PVI) only. Modulation of the autonomic nervous system by RDN has been shown not only to reduce blood pressure but also to have an antiarrhythmic effect in symptomatic AF patients when the strategy is combined with PVI, thus opening up new therapeutic scenarios.

Renal arteries denervation with second generation systems: a remedy for resistant hypertension?

Initial studies on renal denervation (RDN) for the treatment of non-controlled arterial hypertension (HTN) through radiofrequency ablation of renal arteries demonstrated that RDN is an effective therapeutic strategy to reduce arterial blood pressure (BP). Nonetheless, the first randomized study, SYMPLICITY-HTN-3, failed to demonstrate a clear benefit for RND over the control group. Technologic evolution, with the introduction of new second generation multi-electrode devices, allowed deep energy delivery along the full circumference of the vessel. Two recent randomized studies involving patients assuming (SPYRAL HTN-ON MED) or not (SPYRAL HTN-OFF MED) antihypertensive pharmacologic treatment, demonstrated the efficacy and safety of RDN using second generation systems for radiofrequency ablation. Another recent randomized study demonstrated that RDN with ultrasounds (RADIANCE-HTN SOLO) of the main renal arteries led to a significant BP reduction compared to the control group. These studies have once again raised the interest of the scientific community towards attempting to define the appropriate role of RDN in the treatment of hypertension. Nonetheless, larger and longer clinical trials will be necessary to draw further conclusions.

The role of regioregularity, crystallinity, and chain orientation on electron transport in a high-mobility n-type copolymer.

We investigated the correlation between the polymer backbone structural regularity and the charge transport properties of poly{[N,N'-bis(2-octyldodecyl)-1,4,5,8-naphthalenediimide-2,6-diyl]-alt-5,5'-(2,2'-bithiophene)} [P(NDI2OD-T2)], a widely studied semiconducting polymer exhibiting high electron mobility and an unconventional micromorphology. To understand the influence of the chemical structure and crystal packing of conventional regioregular P(NDI2OD-T2) [RR-P(NDI2OD-T2)] on the charge transport, the corresponding regioirregular polymer RI-P(NDI2OD-T2) was synthesized. By combining optical, X-ray, and transmission electron microscopy data, we quantitatively characterized the aggregation, crystallization, and backbone orientation of all of the polymer films, which were then correlated to the electron mobilities in electron-only diodes. By carefully selecting the preparation conditions, we were able to obtain RR-P(NDI2OD-T2) films with similar crystalline structure along the three crystallographic axes but with different orientations of the polymer chains with respect to the substrate surface. RI-P(NDI2OD-T2), though exhibiting a rather similar LUMO structure and energy compared with the regioregular counterpart, displayed a very different packing structure characterized by the formation of ordered stacks along the lamellar direction without detectible π-stacking. Vertical electron mobilities were extracted from the space-charge-limited currents in unipolar devices. We demonstrate the anisotropy of the charge transport along the different crystallographic directions and how the mobility depends on π-stacking but is insensitive to the degree or coherence of lamellar stacking. The comparison between the regioregular and regioirregular polymers also shows how the use of large planar functional groups leads to improved charge transport, with mobilities that are less affected by chemical and structural disorder with respect to classic semicrystalline polymers such as poly(3-hexylthiophene).

Intracoronary imaging guidance of percutaneous coronary interventions: how and when to apply validated metrics to improve the outcome.

Percutaneous coronary intervention (PCI) is still burdened by a substantial number of complications despite constant technological advances, including the advent of intracoronary imaging (ICI) techniques. ICI modalities have been instrumental for the understanding the mechanism of PCI failure. Thanks to the ability to detail the pre-intervention coronary anatomy and identify the features indicative of sub-optimal stent deployment, ICI techniques can be utilised to improve coronary interventions in different clinical scenarios. More recently large randomized clinical trials on ICI guidance confirmed the clinical effectiveness of this approach especially in complex high-risk interventions.

Independent role of atherosclerotic plaque composition and extension in predicting the risk of cardiac events: a CLIMA substudy.

To investigate two different approaches to determine patient risk to develop cardiac events: the burden of coronary atherosclerosis, as assessed by the Gensini score, and plaque morphology, as assessed by intracoronary optical coherence tomography (OCT). We assessed the Gensini score and OCT features of plaque vulnerability in 847 patients from the CLIMA registry. Patients were divided into four Gensini quartiles. The main study endpoint was the 1-year composite of cardiac death, myocardial infarction (MI) and/or target vessel revascularization (TVR). A total of 56 patients (6.6%) experienced the one-year main composite endpoint. The composite endpoint was significantly affected by the Gensini score (hazard ratio [HR] 1.42, 95% confidence interval [CI] 1.11-1.81, p = 0.005), with a low incidence in the first Gensini quartile (Q1 1.3%) and a higher incidence in the remaining groups (Q2 8.3%, Q3 8.9% and Q4 8.3%). At the multivariable analysis, the combined four OCT criteria (HR 6.4, 95%CI 3.0-13.7, p < 0.001), thin fibrous cap (HR 2.9, 95%CI 1.7-5.0, p < 0.001), lipid arc > 180° (HR 2.1, 95%CI 1.2-3.6, p = 0.010), minimum lumen area < 3.5 mm2 (HR 1.7, 95%CI 1.01-3.0, p = 0.047) and the Gensini score (HR 1.4, 95%CI 1.1-1.8, p = 0.017) were independent predictors of the main composite endpoint. In this post-hoc analysis of the CLIMA study, the burden of coronary atherosclerosis as assessed by the Gensini score and OCT plaque characteristics were independent predictors of cardiac events. Patients with the largest atherosclerosis burden and with plaque vulnerability by OCT were at the highest risk of poor outcome. Clinicaltrials.gov identifier: NCT02883088.

Temperature-independent singlet exciton fission in tetracene.

We use transient absorption spectroscopy to demonstrate that the dynamics of singlet exciton fission in tetracene are independent of temperature (10­270 K). Low-intensity, broad-band measurements allow the identification of spectral features while minimizing bimolecular recombination. Hence, by directly observing both species, we find that the time constant for the conversion of singlets to triplet pairs is ~90 ps. However, in contrast to pentacene, where fission is effectively unidirectional, we confirm that the emissive singlet in tetracene is readily regenerated from spin-correlated "geminate" triplets following fission, leading to equilibrium dynamics. Although free triplets are efficiently generated at room temperature, the interplay of superradiance and frustrated triplet diffusion contributes to a nearly 20-fold increase in the steady-state fluorescence as the sample is cooled. Together, these results require that singlets and triplet pairs in tetracene are effectively degenerate in energy, and begin to reconcile the temperature dependence of many macroscopic observables with a fission process which does not require thermal activation.

Sex-specific features of optical coherence tomography detected plaque vulnerability related to clinical outcomes: insights from the CLIMA study.

PURPOSE: To investigate the different impact of optical coherence tomography (OCT)-derived vulnerable plaque features on future adverse events (AEs) according to the biological sex. METHODS: The prospective multicenter CLIMA study (ClinicalTrials.gov: NCT02883088) enrolled 1003 patients with OCT plaque analysis of non-treated coronary plaques located in the proximal left anterior descending artery. Sex-specific differences in plaque composition and vulnerable features were described. We investigated the incidence of AEs, including cardiac death, any myocardial infarction and target vessel revascularization at 1-year. RESULTS: Among 1003 patients, 24.6% were women. Women were older and more frequently affected by chronic kidney disease. Dyslipidemia, prior MI and smoking habit were more common in men. At OCT analysis, women had shorter plaque length (p < 0.001), ticker fibrous cap (p = 0.001), smaller maximum lipid arc (p = 0.019), lower macrophage infiltration (p < 0.001) and intra-plaque layered tissue (p = 0.007). During follow-up, 65 AEs were registered. The presence of a thin fibrous cap and a large macrophage infiltration (> 67°) predicted AEs in both sexes. The presence of macrophages (HR 3.38, p = 0.018) and a small minimum lumen area (HR 4.97, p = 0.002) were associated with AEs in women but not in men, while a large lipid arc (> 180°) was associated with AEs in men (HR 2.56, p = 0.003) but not in women. CONCLUSION: This subanalysis of the CLIMA study investigated for the first-time sex-specific OCT features of plaque vulnerability associated with AEs. Local inflammation was associated with AEs in women and a large lipid arc was predictive in men. OCT may help develop sex-specific risk stratification strategies.

Optical coherence tomography-derived lipid core burden index and clinical outcomes: results from the CLIMA registry.

AIMS: The aim of this study was to assess the morphological characteristics and prognostic implications of the optical coherence tomography (OCT)-derived lipid core burden index (LCBI). METHODS AND RESULTS: OCT-LCBI was assessed in 1003 patients with 1-year follow-up from the CLIMA multicentre registry using a validated software able to automatically obtain a maximum OCT-LCBI in 4 mm (maxOCT-LCBI4mm). Primary composite clinical endpoint included cardiac death, myocardial infarction, and target-vessel revascularization. A secondary analysis using clinical outcomes of CLIMA study was performed. Patients with a maxOCT-LCBI4mm ≥ 400 showed higher prevalence of fibrous cap thickness (FCT) <75 µm [odds ratio (OR) 1.43, 95% confidence interval (CI) 1.03-1.99; P = 0.034], lipid pool arc >180° (OR 3.93, 95%CI 2.97-5.21; P < 0.001), minimum lumen area <3.5 mm2 (OR 1.5, 95%CI 1.16-1.94; P = 0.002), macrophage infiltration (OR 2.38, 95%CI 1.81-3.13; P < 0.001), and intra-plaque intimal vasculature (OR 1.34, 95%CI 1.05-1.72; P = 0.021). A maxOCT-LCBI4mm ≥400 predicted the primary endpoint [adjusted hazard ratio (HR) 1.86, 95%CI 1.1-3.2; P = 0.019] as well as the CLIMA endpoint (HR 2.56, 95%CI 1.24-5.29; P = 0.011). Patients with high lipid content and thin FCT < 75 µm were at higher risk for adverse events (HR 4.88, 95%CI 2.44-9.72; P < 0.001). CONCLUSIONS: A high maxOCT-LCBI4mm was related to poor outcome and vulnerable plaque features. This study represents a step further in the automated assessment of the coronary plaque risk profile.

Spectroscopic investigation of oxygen- and water-induced electron trapping and charge transport instabilities in n-type polymer semiconductors.

We present an optical spectroscopy study on the role of oxygen and water in electron trapping and storage/bias-stress degradation of n-type polymer field-effect transistors based on one of the most widely studied electron transporting conjugated polymers, poly{[N,N9-bis(2-octyldodecyl)-naphthalene-1,4,5,8-bis(dicarboximide)-2,6-diyl]-alt-5,59-(2,29-bisthiophene)} (P(NDI2OD-T2)). We combine results obtained from charge accumulation spectroscopy, which allow optical quantification of the concentration of mobile and trapped charges in the polymer film, with electrical characterization of P(NDI2OD-T2) organic field-effect transistors to study the mechanism for storage and bias-stress degradation upon exposure to dry air/oxygen and humid nitrogen/water environments, thus separating the effect of the two molecules and determining the nature of their interaction with the polymer. We find that the stability upon oxygen exposure is limited by an interaction between the neutral polymer and molecular oxygen leading to a reduction in electron mobility in the bulk of the semiconductor. We use density functional theory quantum chemical calculations to ascribe the drop in mobility to the formation of a shallow, localized, oxygen-induced trap level, 0.34 eV below the delocalized lowest unoccupied molecular orbital of P(NDI2OD-T2). In contrast, the stability of the polymer anion against water is limited by two competing reactions, one involving the electrochemical oxidation of the polymer anion by water without degradation of the polymer and the other involving a radical anion-catalyzed chemical reaction of the polymer with water, in which the electron can be recycled and lead to further degradation reactions, such that a significant portion of the film is degraded after prolonged bias stressing. Using Raman spectroscopy, we have been able to ascribe this to a chemical interaction of water with the naphthalene diimide unit of the polymer. The degradation mechanisms identified here should be considered to explain electron trapping in other rylene diimides and possibly in other classes of conjugated polymers as well.

[From regression to stabilization: new insights into the evolution of coronary atherosclerotic plaque]. / Dalla regressione alla stabilizzazione: l'evoluzione della placca aterosclerotica coronarica secondo le nuove evidenze.

Coronary artery atherosclerosis is a constantly evolving disease. Over the years, new drug therapies have been shown to reduce adverse cardiovascular events and improve the survival of patients with coronary artery disease. New intracoronary imaging modalities, including intravascular ultrasound, optical coherence tomography, and near-infrared spectroscopy, have been introduced to detect the anatomic changes which follow an effective lipid-lowering therapy in human coronary plaques. Particularly, the use of optical coherence tomography made it possible to evaluate plaque composition and showed how an intensive lipid-lowering therapy can stabilize atherosclerosis by improving vulnerable plaque features. Future non-invasive applications are required for large-scale use of these findings.

Reduction in emergency access for acute myocardial infarction during the COVID-19 pandemic: a survey from the greater area of Rome.

BACKGROUND: On March 9, 2020, the Italian government imposed a national lockdown to tackle the COronaVIrus Disease 19 (COVID-19) pandemic, including stay at home recommendations. The precise impact of COVID-19 scare and lockdown on emergency access for acute myocardial infarction (MI) is still subject to debate. METHODS: Data on all patients undergoing invasive coronary angiography at 9 hospitals in the greater area of Rome, Italy, between February 19, 2020 and March 29, 2020 were retrospectively collected. Incidence of ST-elevation MI (STEMI), and non-ST-elevation MI (NSTEMI), as well as corresponding percutaneous coronary intervention (PCI), was compared distinguishing two different 20-day time periods (before vs. on or after March 10, 2020). RESULTS: During the study period, 1068 patients underwent coronary angiography, 142 (13%) with STEMI and 169 (16%) with NSTEMI. The average daily number of STEMI decreased from 4.3 before the lockdown to 2.9 after the lockdown (P=0.021). Similarly, the average daily number of NSTEMI changed from 5.0 to 3.5 (P=0.028). The average daily number of primary PCI changed from 4.2 to 2.9 (P=0.030), while the average daily number of PCI for NSTEMI changed from 3.5 to 2.5 (P=0.087). For STEMI patients, the time from symptom onset to hospital arrival (onset-to-door time less than three hours) showed a significant increase after the lockdown (P=0.018), whereas door-to-balloon time did not change significantly from before to after the lockdown (P=0.609). CONCLUSIONS: The present study, originally reporting on the trends in STEMI and NSTEMI in the Rome area, highlights that significant decreases in the incidence of both acute coronary syndromes occurred between February 19, 2020 and March 29, 2020, together with increases in time from symptom onset to hospital arrival, luckily without changes in door-to-balloon time.

The Role of the Association Between Serum C-Reactive Protein Levels and Coronary Plaque Macrophage Accumulation in Predicting Clinical Events - Results from the CLIMA Registry.

The present investigation aims to study the interaction between systemic and intra-plaque inflammation in predicting cardiac events. We investigated C-reactive protein (CRP) levels as well as plaque inflammation with optical coherence tomography (OCT)-detected macrophages in the CLIMA study. 689 patients had admission CRP serum values reported, and high CRP values were defined as ≥ 2 mg/dl. The main study endpoint was a composite of cardiac death, myocardial infarction, and/or target vessel revascularization at 1-year follow-up. At multivariate Cox regression analysis, a large (hazard ratio [HR] 2.27, 95% confidence interval [CI] 1.2-4.3; p = 0.013) and superficial (HR 2.78, 95%CI 1.5-5.1; p = 0.001) macrophage arc was predicted of the main composite endpoint in patients with high CRP levels. Patients with large/superficial macrophage accumulation and low CRP levels were not at higher risk of adverse events. The presence of high CRP levels and large/superficial macrophage accumulation at OCT analysis identified patients at higher risk of clinical events.

Impact of weather and pollution on the rate of cerebrovascular events in a large metropolitan area.

BACKGROUND: Despite mounting evidence, there is uncertainty on the impact of the interplay between weather and pollution features on the risk of acute cerebrovascular events (CVE). We aimed at appraising role of weather and pollution on the daily risk of CVE. METHODS: Anonymized data from a hub CVE center in a large metropolitan area were collected and analyzed according to weather (temperature, pressure, humidity, and rainfall) and pollution (carbon monoxide [CO], nitrogen dioxide [NO2], nitrogen oxides [NOX], ozone [O3], and particulate matter [PM]) on the same and the preceding days. Poisson regression and time series analyses were used to appraise the association between environmental features and daily CVE, distinguishing also several subtypes of events. RESULTS: We included a total of 2534 days, with 1363 days having ≥1 CVE, from 2012 to 2017. Average daily rate was 1.56 (95% confidence interval: 1.49; 1.63) for CVE, with other event rates ranging between 1.42 for stroke and 0.01 for ruptured intracranial aneurysm. Significant associations were found between CVE and temperature, pressure, CO, NO2, NOX, O3, and PM <10 µm (all P<0.05), whereas less stringent associations were found for humidity, rainfall, and PM <2.5 µm. Time series analysis exploring lag suggested that associations were stronger at same-day analysis (lag 0), but even environmental features predating several days or weeks were significantly associated with events. Multivariable analysis suggested that CO (point estimate 1.362 [1.011; 1.836], P=0.042) and NO2 (1.011 [1.005; 1.016], P<0.001) were the strongest independent predictors of CVE. CONCLUSIONS: Environmental features are significantly associated with CVE, even several days before the actual event. Levels of CO and NO2 can be potentially leveraged for population-level interventions to reduce the burden of CVE.

Left ventricular systolic performance is improved in elite athletes.

AIMS: We sought to investigate the systolic time interval (STI) and efficiency of left ventricular (LV) contraction comparatively in elite athletes and healthy sedentary controls by means of three-dimensional echocardiography (3DE). METHODS AND RESULTS: Four hundred and twenty-nine elite athletes, involved in skill (n = 41), power (n = 63), mixed (n = 167), and endurance (n = 158) disciplines and 98 sedentary controls, matched for age, underwent 3DE. By off-line analysis, we measured the absolute and relative (normalized by the R-R interval) timing of LV systolic emptying (STI and STI%) and the systolic flow velocity (SFV = stroke volume/STI). Both STI and STI% were shorter in athletes, regardless of the sport discipline, compared with controls (respectively, 324 ± 36 vs. 345 ± 33 ms, P < 0.001; 30 ± 4 vs. 40 ± 4%; P< 0.001). Regression analysis showed that heart rate was the most important determinant of STI (R(2) = 0.38; P < 0.001), while age, body surface area, blood pressure, LV volumes, and mass had no significant association. After removing the effects of heart rate and gender, athletes showed a significant reduction (by 50.4 ms; 95% confidence interval, from 57.7 to 43.1) in STI compared with untrained subjects. Finally, higher SFV were identified in skill (256 ± 60 mL/s; P < 0.001), strength (297 ± 78 mL/s; P < 0.001), mixed (308 ± 67 mL/s; P < 0.001), and endurance (334 ± 74 mL/s; P < 0.001) athletes compared with controls (204 ± 50 mL/s). CONCLUSION: Elite athletes show a significant shortening of the systolic time duration in comparison with sedentary controls, in association with a significant increase in LV emptying velocity. This pattern characterizes the physiological LV adaptation of the athletes and may potentially be useful in differential diagnosis of the 'athlete heart'.

Complications during chronic total occlusion percutaneous coronary intervention: a sign- and symptom-based approach to early diagnosis and treatment.

Coronary chronic total occlusions (CTO) are frequently found in patients undergoing coronary angiography. Despite their high prevalence and indication for revascularization in a relevant proportion of cases, CTO recanalization is attempted only in a minority of cases. This is due to higher risk of procedural complications compared to non-CTO interventions and because CTO-PCIs are the most complex procedures in interventional cardiology. In particular, the perceived higher risk of complications during CTO interventions might discourage new operators from engaging in this challenging field. The aim of this work was to review the potential complications of CTO percutaneous coronary intervention, and to provide an algorithmic, sign- and symptom-based approach to facilitate early recognition and effective management.

Perclose Proglide™ for vascular closure.

In the past 20 years, numerous percutaneous vascular closure devices have been tested and compared with manual compression and to surgical cut-down. The suture-mediated closure device Perclose ProGlide™ system (Abbott Vascular, CA, USA) emerged as a safe and effective alternative for many procedures requiring either small or large bore vascular accesses. In this review, we will discuss the characteristics of this vascular closure device and the main studies that proved its potential to reduce vascular complications, time to deambulation, time to discharge and patient discomfort.