Manuel Teixeira

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.

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.

Hypertension is the most determinant risk factor for cardiovascular diseases. Early intervention and future therapies targeting hypertension mechanisms may improve the quality of life and clinical outcomes. Hypertension has a complex multifactorial aetiology and was recently associated with protein homeostasis (proteostasis). This work aimed to characterize proteostasis in easy-to-access plasma samples from 40 individuals, 20 with controlled hypertension and 20 age- and gender-matched normotensive individuals. Proteostasis was evaluated by quantifying the levels of protein aggregates through different techniques, including fluorescent probes, slot blot immunoassays and Fourier-transform infrared spectroscopy (FTIR). No significant between-group differences were observed in the absolute levels of various protein aggregates (Proteostat or Thioflavin T-stained aggregates; prefibrillar oligomers and fibrils) or total levels of proteostasis-related proteins (Ubiquitin and Clusterin). However, significant positive associations between Endothelin 1 and protein aggregation or proteostasis biomarkers (such as fibrils and ubiquitin) were only observed in the hypertension group. The same is true for the association between the proteins involved in quality control and protein aggregates. These results suggest that proteostasis mechanisms are actively engaged in hypertension as a coping mechanism to counteract its pathological effects in proteome stability, even when individuals are chronically medicated and presenting controlled blood pressure levels.

It is widely accepted that exercise training has beneficial effects on vascular health. Although a dose-dependent relation has been suggested, little is known about the effects of different exercise durations on endothelial markers. This study aimed to assess the effect of single exercise sessions with different durations in the circulating levels of endothelial progenitor cells (EPCs) and endothelial cells (CECs) among adults with cardiovascular risk factors. Ten participants performed two multicomponent exercise sessions, one week apart, lasting 30 and 45 min (main exercise phase). Before and after each exercise session, blood samples were collected to quantify EPCs and CECs by flow cytometry. The change in EPCs was significantly different between sessions by 3.0% (95% CI: 1.3 to 4.7), being increased by 1.8 ± 1.7% (p = 0.009) in the 30 min session vs. −1.2 ± 2.0% (p > 0.05) in the 45 min session. No significant change was observed in CECs [−2.0%, 95%CI: (−4.1 to 0.2)] between the sessions. In conclusion, a multicomponent exercise session of 30 min promotes an acute increase in the circulating levels of EPCs without increasing endothelial damage (measured by the levels of CECs) among adults with cardiovascular risk factors.

Introduction: Resistant hypertension is a major challenge of modern cardiovascular medicine, as it is a puzzling problem without a clear solution. Exercise training clearly reduces blood pressure (BP) and oxidative stress in patients with hypertension, however evidence is limited regarding resistant hypertension. Purpose: To determine the effect of an aerobic exercise training program in BP, angiotensin II and oxidative stress in patients with resistant hypertension. Methods: EnRicH is a prospective, two-center, single-blinded, randomized controlled trial with a parallel two-arm group. Sixty patients with resistant hypertension were randomly assigned in a 1:1 ratio to undergo a 12-week aerobic exercise training program (exercise) or usual care (control). The powered primary efficacy measure was 24-hour ambulatory systolic BP change from baseline. Secondary outcome measures included daytime and nighttime ambulatory BP, office BP, cardiorespiratory fitness, and oxidative stress and inflammatory biomarkers: Interferon-gamma (IFN-y), Angiotensin II, vascular endothelial growth factor (VEGF), and superoxide dismutase (SOD). Results: Fifty-three patients (exercise n=26, control n=27) completed the study. Patients were mainly women (54.7%), with an office BP of 140.7±15.9/84.2±9.4 mm Hg and taking an average of 4.6 antihypertensive medications (median, 5; range, 3 to 7). At baseline, no differences were found between groups for the study outcomes and patient characteristics. Ambulatory systolic BP was reduced −7.1 mm Hg (95% CI, −12.8 to −1.4; P=0.015) in the exercise group (127.4±12.2 to 121.2±12.2, p=0.007) compared to control group (126.1±17.2 to 126.9±15.2, p=514) over 24-hour. In addition, 24-hour ambulatory diastolic BP (−5.1 mm Hg, −7.9 to −2.3, P=0.001), daytime ambulatory systolic (−8.4 mm Hg, −14.3 to −2.5, P=0.006), and diastolic BP (−5.7 mm Hg, −9.0 to −2.4, P=0.001) were also reduced in the exercise group compared to the control group. There were no differences in the change of nighttime ambulatory BP between groups. Cardiorespiratory fitness improved in the exercise group by 14% (4.7 ml.kg-1.min-1, P<0.001), while it remained unchanged in the control group (−0.37 ml.kg-1.min-1, P=0.442). A significant between-group difference in favor of exercise group was found for IFN-y (−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), VEGF (10.53 pg/mL, 95% CI: 0.60 to 22.54; P=0.035), and SOD (0.35 pg/mL, 95% CI: 0.10 to 0.58; P=0.009). Conclusions: A 12-week moderate intensity aerobic exercise program reduced ambulatory BP, angiotensin II and oxidative stress in patients with resistant hypertension. The antihypertensive effects of exercise in patients with resistant hypertension may be mediated by positive changes in oxidative stress and inflammatory biomarkers. Funding Acknowledgement: Type of funding sources: Foundation. Main funding source(s): European Union through European Regional Development Fund – Operational Competitiveness Factors Program (COMPETE)Portuguese Government through FCT - Foundation for Science and Technology

BACKGROUND: Physical exercise is a well-established strategy to control blood pressure. Nonetheless, its effects on protein homeostasis in individuals with hypertension are not clearly defined. AIMS: Evaluate proteostasis, quality of life, and inflammation, oxidative stress, and vasoactive biomarkers in adults with hypertension regarding reported exercise habits. METHODS: Twenty individuals were recruited in a health-care centre, 10 regular exercisers (age: 68.3 ± 4.2 years) and 10 age-matched individuals without regular exercise participation (age: 67.7 ± 5.1 years). Proteostasis and the levels of ubiquitin, heat shock protein 70 (Hsp70), endothelial nitric oxide synthase (eNOS), matrix metalloproteinases 2 (MMP-2), tissue inhibitor of MMP-2 (TIMP-2), connexin 43 (Cx43) and extracellular superoxide dismutase-3 (SOD-3) were assessed in plasma using immunoblotting techniques (western blot or slot blot) and Fourier-transform infrared spectroscopy (FTIR). Quality of life was assessed using the Short Form 36 (SF-36) version 2.0 questionnaire. RESULTS: Significant higher levels of interleukin (IL)-6 (P = 0.014), eNOS (P = 0.011), Cx43 (P = 0.020), TIMP-2 (P = 0.038), and SOD-3 (P = 0.001), with a fold increase of 1.5, 1.2, 2.1, 1.3, and 1.2, respectively, were found in the exercise group. The overall quality of life (60.1 ± 4.3 vs. 53.2 ± 5.9, P = 0.009), as well as mental health domain (59.4 ± 7.9 vs. 50.7 ± 7.2, P = 0.024) were significantly higher in the exercise group. Multivariate analysis by FTIR showed that the age-matched group is characterized by peaks related with antiparallel β-sheet, whereas exercise group is characterized by peaks related to random coils, β-sheet, and α-helix. CONCLUSIONS: Individuals with regular exercise participation showed better proteostasis, quality of life, inflammatory profile, antioxidant defenses, and eNOS levels.