This study investigated proteomic alterations in the pulmonary circulation of patients with pulmonary arterial hypertension associated with systemic sclerosis (PAH-SSc) by analyzing the transpulmonary protein gradient and comparing the proteomic profiles with systemic sclerosis (SSc) without PAH. Twenty women were included (10 PAH-SSc, 64.6 ± 10.8 years; 10 SSc, 62.8 ± 11.5 years). The transpulmonary gradient was defined as the difference in biomarker concentrations between wedge-position and pulmonary artery blood samples. Peptides were analysed using liquid chromatography-mass spectrometry, and differentially abundant proteins were identified with Proteome Discoverer. Protein-protein interaction networks were generated with STRING and visualized in Cytoscape. A total of 270 proteins were detected, with no significant transpulmonary gradient alterations. However, patients with PAH-SSc showed distinct proteomic profiles compared to SSc. Multivariate analysis identified 48 differentially abundant proteins in pulmonary artery plasma, with 15 overrepresented and 33 downregulated in PAH-SSc. Among these, the downregulation of transforming growth factor-beta-induced protein ig-h3 (TGFβI/ig-h3) points to a potential involvement of the TGF-β-related extracellular matrix remodelling pathway in PAH-SSc. However, further validation in larger and independent cohorts is required before its relevance as a biomarker or therapeutic target can be established. In conclusion, while no transpulmonary proteomic gradient was observed, the proteomic profiles of PAH-SSc and SSc were different. The profile in PAH-SSc was characterized by differences in immune response, lipid metabolism, and hemostatic proteins. Significance This study offers the first proteomic characterization of the transpulmonary gradient in PAH-SSc and SSc. Although no differences in the gradient were found, the pulmonary artery plasma proteome of PAH-SSc patients showed a distinct pattern compared to SSc. Several proteins associated with immune function, haemostasis, and cellular processes were altered, which may indicate specific pathophysiological features of PAH-SSc or suggest how lung dysfunction develops in SSc. Targeting dysregulated proteins like TGFβI/ig-h3 or addressing immune-coagulation imbalances may support future research studies. Overall, these findings refine the molecular profile of PAH-SSc and provide a basis for future large-scale studies aimed at clarifying disease mechanisms and identifying clinically relevant molecular signatures.

BACKGROUND:Hypertension is a multifactorial condition that is likely to affect older adults. We evaluated the effects of home-based isometric handgrip training (IHT) or aerobic exercise training (AET) on vascular health of older adults with elevated blood pressure (BP) and hypertension. METHODS:The HoldAge trial (NCT04275032) was a two-center prospective randomized controlled trial. Eighty-four participants (46 women, 71.1 ± 3.6 years, BP: 137.1 ± 13.8/80.8 ± 8.3 mmHg) were randomized into IHT, AET, or usual medical care. Participants performed IHT or AET three times/week for 8 weeks. IHT consisted of 4 × 45 bilateral contractions at 50% of maximum voluntary contraction with 1-min rest between sets. AET consisted of walking 30 min at 50-70% of maximum oxygen consumption. Usual medical care received standard medical care. Outcome comprised blood pressure variability (BPV), flow-mediated dilation (FMD), aortic pulse wave velocity (aoPWV), and endothelial function and inflammation biomarkers. RESULTS:No significant group × time interaction effects occurred for 24-h and daytime BPV, FMD, aoPWV, and circulating biomarkers (P > 0.05). A significant group × time interaction occurred for nighttime systolic BPV (P = 0.005). IHT decreased nighttime systolic BPV over time (-1.5 ± 3.0 mmHg; P = 0.011), while AET (1.1 ± 2.9 mmHg; P = 0.064) and usual medical care (0.6 ± 2.7 mmHg; P = 0.344) did not. CONCLUSION:Home-based IHT effectively reduces nighttime systolic BPV in older adults with elevated BP and hypertension, suggesting it could serve as a valuable nonpharmacological strategy to improve vascular health.

Magalhães, Sandra MD; Santos, Mário PhD; Viamonte, Sofia PhD; Teixeira, Manuel MSc; Ribeiro, Fernando PhD; Cyrne-Carvalho, Henrique PhD Author Information

Introduction: The limited accessibility and the lack of adherence explain, in part, the low proportion of heart failure (HF) patients undergoing exercise -based cardiac rehabilitation (CR) programs. Home -based programs showed to be as effective and less costly than centre -based ones and might address those obstacles. Whether the evidence from international studies can be applied to our population is still unclear. Objectives: To compare the clinical and economic impact of a home -based versus centre -based CR intervention in HF patients. Methods: This is a single -center, single-blind, parallel groups, non -inferiority pragmatic randomized control trial. Adult HF patients (n=120) will be randomized to either a centre -based or home -based CR program. In both groups' patients will participate in a 12 -week combined CR program with 2 sessions per week. Exercise training (ExT) protocol consists of a combination bands). Those allocated to the home-based program will start with 4--5 supervised ExT sessions to familiarize themselves with the training protocol and then will continue the remaining sessions at home. The primary endpoint is the change in VO2peak at the end of the 12-week program. Secondary outcomes include alterations in circulating biomarkers, physical fitness, physical activity, quality of life, diet, psychological wellbeing, dyspnea, and cost-effectiveness Results: Patients are currently being recruited for the study. The study started in November 2019 and data collection is anticipated to be completed by December 2022. This is the first study in Portugal comparing the traditional CR program with a home-based program in HF patients. Our study results will better inform healthcare professionals who care for HF patients regarding (c) 2023 Sociedade Portuguesa de Cardiologia. Published by Elsevier Espana, S.L.U. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by

OBJECTIVE:This trial analyzes the effects of home-based isometric handgrip training (IHT) and aerobic exercise training (AET) on ambulatory and office blood pressure (BP) in older adults with high normal to established hypertension. METHODS:This randomized controlled trial included 84 participants (46 women, 71.1 ± 3.6 years, systolic BP [SBP] 137.1 ± 13.8 mmHg, diastolic BP [DBP] 80.8 ± 8.3 mmHg). Participants were randomized into IHT (n = 28), AET (n = 28), or usual medical care plus lifestyle advice (UC, n = 28). Participants performed IHT or AET three times/week for 8 weeks. IHT consisted of 4 × 45 s bilateral contractions at 50% of maximum voluntary contraction with 1-min rest between sets. AET consisted of walking 30 min at 50%-70% of estimated maximum oxygen consumption. UC received standardized medical care including lifestyle advice. RESULTS:Seventy-six participants completed the intervention: 27 in IHT, 26 in AET, and 23 in UC. At baseline, BP values were similar among groups. No differences were observed in 24-h ambulatory, daytime, and nighttime SBP and DBP in any group (p > 0.05). IHT and AET reduced office SBP (-8.0 ± 13.4 mmHg; p = 0.004; -5.6 ± 12.2 mmHg; p = 0.027, respectively). IHT reduced office DBP (-3.3 ± 7.4 mmHg; p = 0.024), but AET did not. No differences occurred in office BP in UC. There was no difference in office BP among groups (p > 0.05). CONCLUSIONS:An 8-week home-based IHT and AET failed to reduce ambulatory SBP, while office SBP was reduced by 8/5 mmHg. Only IHT reduced office DBP by 3 mmHg. Thus, IHT and AET may be effective for lowering office BP in older adults with high normal to established hypertension.

Central blood pressure (BP) and BP variability are associated with cardiovascular disease risk. However, the influence of exercise on these hemodynamic parameters is unknown among patients with resistant hypertension. The EnRicH (The Exercise Training in the Treatment of Resistant Hypertension) was a prospective, single-blinded randomized clinical trial (NCT03090529). Sixty patients were randomized to a 12-week aerobic exercise program or usual care. The outcome measures include central BP, BP variability, heart rate variability, carotid-femoral pulse wave velocity, and circulating cardiovascular disease risk biomarkers including high-sensitivity C-reactive protein, angiotensin II, superoxide dismutase, interferon gamma, nitric oxide, and endothelial progenitor cells. Central systolic BP decreased by 12.22 mm Hg (95% CI, −1.88 to −22.57, P = 0.022) as did BP variability by 2.85 mm Hg (95% CI, −4.91 to −0.78, P = 0.008), in the exercise ( n = 26) compared to the control group ( n = 27). Interferon gamma −4.3 pg/mL (95%CI, −7.1 to −1.5, P = 0.003), angiotensin II −157.0 pg/mL (95%CI, −288.1 to −25.9, P = 0.020), and superoxide dismutase 0.4 pg/mL (95%CI, 0.1–0.6, P = 0.009) improved in the exercise compared to the control group. Carotid-femoral pulse wave velocity, heart rate variability, high-sensitivity C-reactive protein, nitric oxide, and endothelial progenitor cells were not different between groups ( P > 0.05). In conclusion, a 12-week exercise training program improved central BP and BP variability, and cardiovascular disease risk biomarkers in patients with resistant hypertension. These markers are clinically relevant as they are associated with target organ damage and increased cardiovascular disease risk and mortality.

BACKGROUND:Proteostasis impairment and the consequent increase of amyloid burden in the myocardium have been associated with heart failure (HF) development and poor prognosis. A better knowledge of the protein aggregation process in biofluids could assist the development and monitoring of tailored interventions. AIM:To compare the proteostasis status and protein's secondary structures in plasma samples of patients with HF with preserved ejection fraction (HFpEF), patients with HF with reduced ejection fraction (HFrEF), and age-matched individuals. METHODS:A total of 42 participants were enrolled in 3 groups: 14 patients with HFpEF, 14 patients with HFrEF, and 14 age-matched individuals. Proteostasis-related markers were analyzed by immunoblotting techniques. Fourier Transform Infrared (FTIR) Spectroscopy in Attenuated Total Reflectance (ATR) was applied to assess changes in the protein's conformational profile. RESULTS:Patients with HFrEF showed an elevated concentration of oligomeric proteic species and reduced clusterin levels. ATR-FTIR spectroscopy coupled with multivariate analysis allowed the discrimination of HF patients from age-matched individuals in the protein amide I absorption region (1700-1600 cm-1), reflecting changes in protein conformation, with a sensitivity of 73 and a specificity of 81%. Further analysis of FTIR spectra showed significantly reduced random coils levels in both HF phenotypes. Also, compared to the age-matched group, the levels of structures related to fibril formation were significantly increased in patients with HFrEF, whereas the β-turns were significantly increased in patients with HFpEF. CONCLUSION:Both HF phenotypes showed a compromised extracellular proteostasis and different protein conformational changes, suggesting a less efficient protein quality control system.

The evidence that physical exercise has multiple beneficial effects and is essential to a healthy lifestyle is widely accepted for a long-time. The functional and psychological changes promoted by exercise improve clinical outcomes and prognosis in several diseases, by decreasing mortality, disease severity, and hospital admissions. Nonetheless, the mechanisms that regulate the release, uptake, and communication of several factors in response to exercise are still not well defined. In the last years, extracellular vesicles have attracted significant interest in the scientific community due to their ability to carry and deliver proteins, lipids, and miRNA to distant organs in the body, promoting a very exciting crosstalk machinery. Moreover, increasing evidence suggests that exercise can modulate the release of those factors within EVs into the circulation, mediating its systemic adaptations.In this chapter, we summarize the effects of acute and chronic exercise on the extracellular vesicle dynamics in healthy subjects and patients with cardiovascular disease. The understanding of the changes in the cargo and kinetics of extracellular vesicles in response to exercise may open new possibilities of research and encourage the development of novel therapies that mimic the effects of exercise.

Purpose of Review Approximately 10% of the adults with hypertension fail to achieve the recommended blood pressure treatment targets on 3 antihypertensive medications or require ≥ 4 medications to achieve goal. These patients with ‘resistant hypertension’ have an increased risk of target organ damage, adverse clinical events, and all-cause mortality. Although lifestyle modification is widely recommended as a first-line approach for the management of high blood pressure, the effects of lifestyle modifications in patients with resistant hypertension has not been widely studied. This review aims to provide an overview of the emerging evidence on the benefits of lifestyle modifications in patients with resistant hypertension, reviews potential mechanisms by which lifestyles may reduce blood pressure, and discusses the clinical implications of the recent findings in this field. Recent Findings Evidence from single-component randomized clinical trials demonstrated that aerobic exercise, weight loss and dietary modification can reduce clinic and ambulatory blood pressure in patients with resistant hypertension. Moreover, evidence from multi-component trials involving exercise and dietary modification and weight management can facilitate lifestyle change, reduce clinic and ambulatory blood pressure, and improve biomarkers of cardiovascular risk. Summary This new evidence supports the efficacy of lifestyle modifications added to optimized medical therapy in reducing blood pressure and improving cardiovascular risk biomarkers in patients with resistant hypertension. These findings need to be confirmed in larger studies, and the persistence of benefit over extended follow-up needs further study.

To evaluate the effects of a multicomponent exercise program in the circulating levels of endothelial progenitor cells (EPCs) and endothelial damage among adults with cardiovascular risk factors. Eleven adults with cardiovascular risk factors underwent an 18-week light-to-moderate intensity multicomponent exercise training program. Participants performed two 45 min supervised sessions per week. Blood samples were collected before and after the exercise program, and the levels of EPCs and circulating endothelial cells (CECs) were quantified by flow cytometry. The circulating levels of EPCs increased by 5.0 ± 3.3

The impact of exercise on the levels of endothelial progenitor cells (EPCs), a marker of endothelial repair and angiogenesis, and circulating endothelial cells (CECs), an indicator of endothelial damage, in heart failure patients is largely unknown. This study aims to evaluate the effects of a single exercise bout on the circulating levels of EPCs and CECs in heart failure patients. Thirteen patients with heart failure underwent a symptom-limited maximal cardiopulmonary exercise test to assess exercise capacity. Before and after exercise testing, blood samples were collected to quantify EPCs and CECs by flow cytometry. The circulating levels of both cells were also compared to the resting levels of 13 volunteers (age-matched group). The maximal exercise bout increased the levels of EPCs by 0.5% [95% Confidence Interval, 0.07 to 0.93%], from 4.2 × 10−3 ± 1.5 × 10−3% to 4.7 × 10−3 ± 1.8 × 10−3% (p = 0.02). No changes were observed in the levels of CECs. At baseline, HF patients presented reduced levels of EPCs compared to the age-matched group (p = 0.03), but the exercise bout enhanced circulating EPCs to a level comparable to the age-matched group (4.7 × 10−3 ± 1.8 × 10−3% vs. 5.4 × 10−3 ± 1.7 × 10−3%, respectively, p = 0.14). An acute bout of exercise improves the potential of endothelial repair and angiogenesis capacity by increasing the circulating levels of EPCs in patients with heart failure.

This study characterizes the plasma levels and composition of SDS-resistant aggregates (SRAs) in patients with heart failure with preserved ejection fraction (HFpEF) to infer molecular pathways associated with disease and/or proteostasis disruption. Twenty adults (ten with HFpEF and ten age-matched individuals) were included. Circulating SRAs were resolved by diagonal two-dimensional SDS-PAGE, and their protein content was identified by mass spectrometry. Protein carbonylation, ubiquitination and ficolin-3 were evaluated. Patients with HFpEF showed higher SRA/total (36.6 ± 4.9

The decrease in intermolecular beta-sheets may represent an improvement in the protein turnover and a better protein quality control in hypertension as a result of IRT. The differences in the antiparallel beta-sheets and beta-turns after IRT indicate IRT is modifying the protein profile. Further studies are needed to confirm these results and to address how exercise is influencing protein homeostasis.

BACKGROUND:A potential relationship between oral health and cardiovascular diseases has been proposed. However, uncertainty remains as to whether there is sufficient data to support this association. This review aims to appraise the relationship between apical periodontitis and cardiovascular disease based on data from observational studies. METHODS:The databases Medline (via PubMed) and EMBASE (via Scopus) were searched up to August 2020 for observational studies (case-control, cross-sectional, and cohort) assessing the association of apical periodontitis with cardiovascular disease among adults. Pooled relative risk/odds ratio and 95% confidence interval (CI) were estimated using a random-effects model. Sensitivity analyses and random-effects meta-regressions were performed. RESULTS:The initial search yielded 2537 documents, of which 15 were eligible for inclusion, including 8 cross-sectional studies, 5 case-control studies, and 2 cohort studies. The majority of studies enrolled both men and women, with mean age ranging from 41 to 66 years. In cross-sectional studies, the presence of apical periodontitis was significantly associated with cardiovascular disease with a combined odds ratio of 1.53 (95% CI: 1.02-2.29, p = 0.039; I2 = 75.0%; p < 0.001). In the case-control studies, the combined odds ratio did not show a significant association of apical periodontitis with cardiovascular disease (OR = 1.24; 95% CI: 0.67-2.29, p = 0.494; I2 = 82.1%; p < 0.001). The pooled risk ratio from the 2 cohort studies showed (RR = 1.27; 95% CI: 0.71-2.27, p = 0.413; I2 = 69.1%; p = 0.072) also showed no significant association between apical periodontitis and cardiovascular disease. These results should be interpreted with caution due to the high heterogeneity. CONCLUSIONS:Data derived from cross-sectional studies suggest a weak association between apical periodontitis and cardiovascular disease. As the results were not consistent across study designs, further research is recommended, namely longitudinal studies with long-term follow-up. REGISTRATION:PROSPERO database (CRD42020204379).

Background. Endothelial dysfunction has been suggested as a potential mechanism contributing to the development and progression of heart failure (HF). Levels of circulating endothelial cells (CECs), endothelial progenitor cells (EPCs), and hematopoietic stem and progenitor cells (HSPCs) have been recognized as useful markers of vascular damage and endothelial repair in response to tissue injury. Aims. To evaluate the circulating levels of EPCs, CECs, and HSPCs among patients with HF with reduced ejection fraction (HFrEF). Methods. In 82 individuals (42 patients with HFrEF and 42 age-matched subjects without established cardiovascular disease), peripheral blood was drawn and levels of EPCs, CECs, and HSPCs were quantified by flow cytometry. Results. Patients with HFrEF showed lower levels of circulating EPCs (5.28 x 10 -3 +/- 6.83 x 10 -4 % vs. 7.76 x 10 -3 +/- 4.91 x 10 -4 %, p <= 0.001) and CECs (5.11 x 10 -3 +/- 7.87 x 10 -4 % vs. 6.51 x 10 -3 +/- 5.21 x 10 -4 %, p = 0.005) when compared to the age-matched group. Circulating levels of HSPCs were not significantly different between groups ( p = 0.590). Additionally, the number of EPCs and CECs was significantly higher in HFrEF patients with overweight/obesity ( n = 24) compared to patients with normal weight ( n = 17). Conclusion. Circulating levels of EPCs and CECs were significantly decreased in patients with HFrEF in comparison to age-matched subjects without established cardiovascular disease, suggesting that the levels of CECs and EPCs may be potential biomarkers of the cellular response to vascular injury in patients with HFrEF. (c) 2022 Instituto Mexicano del Seguro Social (IMSS). Published by Elsevier Inc. All rights reserved.

Exercise adherence in HoldAge is high in both IHT and AET, but the time spent at the prescribed intensity appears to be higher in IHT than AET.