Mechanisms of heart failure and chronic kidney disease protection by SGLT2 inhibitors in nondiabetic conditions.

Sodium-glucose cotransporter 2 inhibitors (SGLT2is), initially developed for type 2 diabetes (T2D) treatment, have demonstrated significant cardiovascular and renal benefits in heart failure (HF) and chronic kidney disease (CKD), irrespective of T2D. This review provides an analysis of the multifaceted mechanisms underlying the cardiorenal benefits of SGLT2i in HF and CKD outside of the T2D context. Eight major aspects of the protective effects of SGLT2i beyond glycemic control are explored: 1) the impact on renal hemodynamics and tubuloglomerular feedback; 2) the natriuretic effects via proximal tubule Na+/H+ exchanger NHE3 inhibition; 3) the modulation of neurohumoral pathways with evidence of attenuated sympathetic activity; 4) the impact on erythropoiesis, not only in the context of local hypoxia but also systemic inflammation and iron regulation; 5) the uricosuria and mitigation of the hyperuricemic environment in cardiorenal syndromes; 6) the multiorgan metabolic reprogramming including the potential induction of a fasting-like state, improvement in glucose and insulin tolerance, and stimulation of lipolysis and ketogenesis; 7) the vascular endothelial growth factor A (VEGF-A) upregulation and angiogenesis, and 8) the direct cardiac effects. The intricate interplay between renal, neurohumoral, metabolic, and cardiac effects underscores the complexity of SGLT2i actions and provides valuable insights into their therapeutic implications for HF and CKD. Furthermore, this review sets the stage for future research to evaluate the individual contributions of these mechanisms in diverse clinical settings.

Renal Function Evolution and Hypoaldosteronism Risk After Unilateral Adrenalectomy for Primary Aldosteronism.

Few studies demonstrated a percentage decrease in the estimated glomerular filtration rate (eGFR) at a single time and the rate of hypoaldosteronism after adrenalectomy for primary aldosteronism (PA). Our aim was to investigate the evolution of renal function and the hypoaldosteronism risk after adrenalectomy for PA. Aldosterone, renin, eGFR, and electrolyte levels were determined before and at 1 week, 1, 3 and 6 months after unilateral adrenalectomy in 94 PA patients (40 men and 54 women). The main outcome was the postoperative eGFR decline using analysis of covariance with the preoperative eGFR as a covariate. eGFR decreased during first postoperative week compared to 3 months before surgery. During the first 6 months, eGFR remained stable at similar levels to the first week after surgery. Age (p=0.001), aldosterone levels (p=0.021) and eGFR 3 months before surgery (p+<+0.0001) had a significant correlation with eGFR during first postoperative week. High aldosterone levels at diagnosis were correlated with decline in renal function in the univariate model (p=0.033). In the multivariate analysis, aldosterone levels at diagnosis had a tendency to be an independent predictor of renal function after surgery (p=0.059). Postoperative biochemical hypoaldosteronism was diagnosed in 48% of the cases after adrenalectomy, but prolonged hyperkalemia occurred in only 4 cases (4.5%). Our findings showed a decrease of eGFR after unilateral adrenalectomy for PA. Additionally, aldosterone levels at diagnosis correlated with postoperative renal function. Postoperative biochemical hypoaldosteronism occurred in almost half of the patients, but prolonged hyperkalemia with fludrocortisone replacement was less frequent.

Bariatric Surgery for Resistant Hypertension: Working in Progress!

PURPOSE OF REVIEW: To discuss the recent evidence pointing the benefits of the bariatric surgery on blood pressure control in patients with obesity and hypertension. Particular focus is devoted to discuss the potential impact on resistant hypertension. RECENT FINDINGS: Growing evidence suggest that bariatric surgery promotes not only a significant reduction in the anti-hypertensive medication while maintained blood pressure control but also a significant proportion of hypertension remission as compared to the usual care. In a sub-analysis of the GATEWAY trial using both office and 24-h ambulatory blood pressure monitoring, the prevalence of resistant hypertension significantly decreased after 12 months in the surgical group whereas the numbers remained stable in the control group. Despite the lack of robust evidence, preliminary findings underscore the strong need to explore the potential role of bariatric surgery on resistant hypertension in patients with obesity. This statement is justified not only for the burden of obesity in this scenario but also for the unmet demands in managing resistant hypertension appropriately by multiple drug-therapy or the lack of real utility of procedures like renal denervation and carotid baroreflex activation.

Is Hypertension a Real Risk Factor for Poor Prognosis in the COVID-19 Pandemic?

PURPOSE OF REVIEW: There is increasing evidence indicating an association between several risk factors and worse prognosis in patients with coronavirus disease 2019 (COVID-19), including older age, hypertension, heart failure, diabetes, and pulmonary disease. Hypertension is of particular interest because it is common in adults and there are concerns related to the use of renin-angiotensin system (RAS) inhibitors in patients with hypertension infected with COVID-19. Levels of angiotensin-converting enzyme 2 (ACE2), a protein that facilitates entry of coronavirus into cells, may increase in patients using RAS inhibitors. Thus, chronic use of RAS inhibition could potentially lead to a more severe and fatal form of COVID-19. In this review, we provide a critical review to the following questions: (1) Does hypertension influence immunity or ACE2 expression favoring viral infections? (2) Are the risks of complications in hypertension mediated by its treatment? (3) Is aging a major factor associated with worse prognosis in patients with COVID-19 and hypertension? RECENT FINDINGS: Despite the potential involvement of immune responses in the pathogenesis of hypertension, there is no evidence supporting that hypothesis that hypertension or RAS inhibitors contributes to unfavorable outcomes in viral infections. Future investigations adopting a strict protocol for confirming hypertension status as well as assessing associated comorbidities that may influence outcomes are necessary. From the therapeutic perspective, recombinant ACE2 may serve as a potential therapy, but relevant studies in humans are lacking. Definitive evidence regarding the use of RAS inhibitors in patients with COVID-19 is needed; 5 randomized trials examining this issue are currently underway. There is no current scientific support for claiming that hypertension or its treatment with RAS inhibitors contribute to unfavorable outcomes in COVID-19.

Effects of ACEi and ARB on post-exercise hypotension induced by exercises conducted at different times of day in hypertensive men.

BACKGROUND: Post-exercise hypotension (PEH) is greater after evening than morning exercise, but antihypertensive drugs may affect the evening potentiation of PEH. Objective: To compare morning and evening PEH in hypertensives receiving angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARB). METHODS: Hypertensive men receiving ACEi (n = 14) or ARB (n = 15) underwent, in a random order, two maximal exercise tests (cycle ergometer, 15 watts/min until exhaustion) with one conducted in the morning (7 and 9 a.m.) and the other in the evening (8 and 10 p.m.). Auscultatory blood pressure (BP) was assessed in triplicate before and 30 min after the exercises. Changes in BP (post-exercise - pre-exercise) were compared between the groups and the sessions using a two-way mixed ANOVA and considering P < .05 as significant. RESULTS: In the ARB group, systolic BP decrease was greater after the evening than the morning exercise, while in the ACEi group, it was not different after the exercises conducted at the different times of the day. Additionally, after the evening exercise, systolic BP decrease was lower in the ACEi than the ARB group (ARB = -11 ± 8 vs -6 ± 6 and ACEi = -6 ± 7 vs. -8 ± 5 mmHg, evening vs. morning, respectively, P for interaction = 0.014). CONCLUSIONS: ACEi, but not ARB use, blunts the greater PEH that occurs after exercise conducted in the evening than in the morning.

Resistant Hypertension: Time to Consider the Best Fifth Anti-Hypertensive Treatment.

PURPOSE OF REVIEW: Resistant hypertension (RH) is a growing clinical condition worldwide associated with target-organ damage and poor prognosis compared to non-resistant counterparts. The purpose of this review is to perform a critical evaluation of preferable drug choices for managing RH highlighting the evidence that significant proportion of patients remained uncontrolled despite using four anti-hypertensive drugs. RECENT FINDINGS: Until recently, the fourth drug therapy was main derived from personal opinion or small interventional studies. The recent data derived from two multicentric randomized trials, namely PATHWAY-2 and ReHOT, pointed spironolactone as the preferable fourth drug therapy in patients with confirmed RH as compared to bisoprolol and doxazosin (PATHWAY-2) as well as clonidine (ReHOT). However, significant proportion of patients (especially observed in ReHOT trial that used 24-h ambulatory blood pressure monitoring) did not achieve optimal blood pressure with the fourth drug. This finding underscores the need of new approaches and treatment options in this important research area. The current evidence pointed that significant proportion of RH patients are requiring more than four drugs for controlling BP. This statement is particularly true considering the new criteria proposed by the 2017 Guidelines for diagnosing RH (> 130 × 80 mmHg). New combinations, drugs, or treatments should be tested aiming to reduce the RH burden. Based on the aforementioned multicentric trials, we proposed the first five preferable anti-hypertensive classes in the overall context of RH.

Post-dynamic, isometric and combined resistance exercise responses in medicated hypertensive men.

This study investigated the effects of dynamic resistance exercise (DRE), isometric handgrip exercise (IHE) and combined resistance exercise (DRE+IHE) on post-exercise hypotension (PEH) and its hemodynamic, autonomic, and vascular mechanisms. For that, 70 medicated hypertensives men (52 ± 8 years) were randomly allocated to perform one of the following interventions: DRE (3 sets, 8 exercises, 50% of 1RM), IHE (4 sets, 2 min, 30% of MVC), CRE (DRE+IHE) and control (CON, seated rest). Before and after the interventions, blood pressure (BP), systemic hemodynamics, cardiovascular autonomic modulation and brachial vascular parameters were evaluated. After the DRE and CRE, systolic and mean BP decreased (SBP = -7 ± 6 and -8 ± 8 mmHg; MBP -4 ± 5 and -5 ± 5 mmHg, respectively, all P < 0.05), vascular conductance increased (+ 0.47 ± 0.61 and +0.40 ± 0.47 ml.min-1.mmHg-1, respectively, both P < 0.05) and baroreflex sensitivity decreased (-0.15 ± 0.38 and -0.29 ± 0.47 ms/mmHg, respectively, both P < 0.05) in comparison to pre-exercise values. No variable presented any significant change after IHE. The responses observed after CRE were similar to DRE and significantly different from CON and IHE. In conclusion, DRE, but not IHE, elicits PEH, which happens concomitantly to skeletal muscle vasodilation and decreased baroreflex sensitivity. Moreover, adding IHE to DRE does not potentiate PEH and neither changes its mechanisms.Clinical Trial Registration: Data from this study derived from an ongoing longitudinal clinical trial approved by the Institution's Ethics Committee of Human Research (process 2.870.688) and registered at the Brazilian Clinical Trials (RBR-4fgknb) at http://www.ensaiosclinicos.gov.br .

Effects of dynamic, isometric, and combined resistance training on ambulatory blood pressure in treated men with hypertension: a randomized controlled trial.

Ambulatory blood pressure (ABP) monitoring is a widespread recommendation for the diagnosis and management of hypertension. Dynamic resistance training (DRT) and isometric handgrip training (IHT) have been recommended for hypertension treatment, but their effects on ABP have been poorly studied. Additionally, combined dynamic and isometric handgrip resistance training (CRT) could produce an additive effect that has yet to be tested. Thus, this randomized controlled trial was designed to evaluate the effects of DRT, IHT and CRT on mean ABP and ABP variability. Fifty-nine treated men with hypertension were randomly allocated to 1 of four groups: DRT (8 dynamic resistance exercises, 50% of 1RM, 3 sets until moderate fatigue), IHT (4 sets of 2 min of isometric handgrip at 30% of MVC), CRT (DRT + IHT) and control (CON - 30 min of stretching). Interventions occurred 3 times/week for 10 weeks, and ABP was assessed before and after the interventions. ANOVAs and ANCOVAs adjusted for pre-intervention values were employed for analysis. Mean 24-h, awake and asleep BPs did not change in either group throughout the study (all, P > 0.05). Nocturnal BP fall as well as the standard deviation, coefficient of variation and the average real variability of ABP also did not change significantly in either group (all, P < 0.05). Changes in all these parameters adjusted to the pre-intervention values were also similar among the four groups (all, p > 0.05). In treated men with hypertension, 10 weeks of DRT, IHT or CRT does not decrease ABP levels nor change ABP variability.

Can blood pressure decrease after maximal exercise test predict the blood pressure lowering effect of aerobic training in treated hypertensive men?

The acute decrease in blood pressure (BP) observed after a session of exercise (called post-exercise hypotension) has been proposed as a tool to predict the chronic reduction in BP induced by aerobic training. Therefore, this study investigated whether post-exercise hypotension observed after a maximal exercise test is associated to the BP-lowering effect of aerobic training in treated hypertensives. Thirty hypertensive men (50 ± 8 years) who were under consistent anti-hypertensive treatment underwent a maximal exercise test (15 watts/min until exhaustion), and post-exercise hypotension was determined by the difference between BP measured before and at 30 min after the test. Subsequently, the patients underwent 10 weeks of aerobic training (3 times/week, 45 min/session at moderate intensity), and the BP-lowering effect of training was assessed by the difference in BP measured before and after the training period. Pearson correlations were employed to evaluate the associations. Post-maximal exercise test hypotension was observed for systolic and mean BPs (-8 ± 6 and -2 ± 4 mmHg, all P < 0.05). Aerobic training reduced clinic systolic/diastolic BPs (-5 ± 6/-2 ± 3 mmHg, both P < 0.05) as well as awake and 24 h mean BPs (-2 ± 6 and -2 ± 5 mmHg, all P < 0.05). No significant correlation was detected between post-exercise hypotension and the BP-lowering effect of training either for clinic or ambulatory BPs (r values ranging from 0.00 to 0.32, all p > 0.05). Post-exercise hypotension assessed 30 min after a maximal exercise test cannot be used to predict the BP-lowering effect of aerobic training in treated hypertensive men.

Effects of dynamic, isometric and combined resistance training on blood pressure and its mechanisms in hypertensive men.

Although dynamic resistance training (DRT) and isometric handgrip training (IHT) may decrease blood pressure (BP) in hypertensives, the effects of these types of training have not been directly compared, and a possible additive effect of combining IHT to DRT (combined resistance training-CRT), has not been investigated. Thus, this study compared the effects of DRT, IHT and CRT on BP, systemic hemodynamics, vascular function, and cardiovascular autonomic modulation. Sixty-two middle-aged men with treated hypertension were randomly allocated among four groups: DRT (8 exercises, 50% of 1RM, 3 sets until moderate fatigue), IHT (30% of MVC, 4 sets of 2 min), CRT (DRT + IHT) and control (CON - stretching). In all groups, the interventions were administered 3 times/week for 10 weeks. Pre- and post-interventions, BP, systemic hemodynamics, vascular function and cardiovascular autonomic modulation were assessed. ANOVAs and ANCOVAs adjusted for pre-intervention values were employed for analysis. Systolic BP decreased similarly with DRT and CRT (125 ± 11 vs. 119 ± 12 and 128 ± 12 vs. 119 ± 12 mmHg, respectively; P < 0.05), while peak blood flow during reactive hyperaemia (a marker of microvascular function) increased similarly in these groups (774 ± 377 vs. 1067 ± 461 and 654 ± 321 vs. 954 ± 464 mL/min, respectively, P < 0.05). DRT and CRT did not change systemic hemodynamics, flow-mediated dilation, and cardiovascular autonomic modulation. In addition, none of the variables were changed by IHT. In conclusion, DRT, but not IHT, improved BP and microvascular function in treated hypertensive men. CRT did not have any additional effect in comparison with DRT alone.

Obstructive sleep apnea and hypertension-mediated organ damage in nonresistant and resistant hypertension.

The potential role of obstructive sleep apnea (OSA) in hypertension-mediated organ damage (HMOD) may be influenced by the presence of resistant hypertension (RH). Herein, we enrolled patients with hypertension from a tertiary center for clinical evaluation and performed a sleep study to identify OSA (apnea-hypopnea index ≥15 events/h) and a blinded analysis of four standard HMOD parameters (left ventricular hypertrophy [LVH], increased arterial stiffness [≥10 m/s], presence of retinopathy, and nephropathy). RH was diagnosed based on uncontrolled blood pressure (BP) (≥140/90 mmHg) despite concurrent use of at least three antihypertensive drug classes or controlled BP with concurrent use of ≥4 antihypertensive drug classes at optimal doses. To avoid the white-coat effect, ambulatory BP monitoring was performed to confirm RH diagnosis. One-hundred patients were included in the analysis (mean age: 54 ± 8 years, 65% females, body mass index: 30.4 ± 4.5 kg/m²). OSA was detected in 52% of patients. Among patients with non-RH (n = 53), the presence of OSA (52.8%) was not associated with an increased frequency of HMOD. Conversely, among patients with RH, OSA (51.1%) was associated with a higher incidence of LVH (RH-OSA,61%; RH + OSA,87%; p = 0.049). Logistic regression analysis using the total sample revealed that RH (OR:7.89; 95% CI:2.18-28.52; p = 0.002), systolic BP (OR:1.04; 95% CI:1.00-1.07; p = 0.042) and OSA (OR:4.31; 95% CI:1.14-16.34; p = 0.032) were independently associated with LVH. No significant association was observed between OSA and arterial stiffness, retinopathy, or nephropathy. In conclusion, OSA is independently associated with LVH in RH, suggesting a potential role of OSA in RH prognosis.

Efficacy of Oral Furosemide Test for Primary Aldosteronism Diagnosis.

Context: Confirmatory tests represent a fundamental step in primary aldosteronism (PA) diagnosis, but they are laborious and often require a hospital environment due to the risks involved. Objective: To evaluate the efficacy of oral furosemide as a new confirmatory test for PA diagnosis. Methods: We prospectively evaluated the diagnostic performance of 80 mg of oral furosemide in 64 patients with PA and 22 with primary hypertension (controls). Direct renin concentration (DRC) was measured before, and 2 hours and 3 hours after the oral furosemide. In addition, the oral furosemide test was compared with 2 other confirmatory tests: the furosemide upright test (FUT) and saline infusion test (SIT) or captopril challenge test (CCT) in all patients with PA. Results: The cut-off of 7.6 µU/mL for DRC at 2 hours after oral furosemide had a sensitivity of 92%, specificity of 82%, and accuracy of 90% for PA diagnosis. In 5 out of 6 controls with low-renin hypertension, which might represent a PA spectrum, renin remained suppressed. Excluding these 6 controls with low-renin hypertension, the DRC cut-off of 10 µU/mL at 2 hours after oral furosemide had a sensitivity of 95.3%, specificity of 93.7% and accuracy of 95% for PA diagnosis. DRC after 3 hours of oral furosemide did not improve diagnostic performance. Using the cut-off of 10 µU/mL, the oral furosemide test and the FUT were concordant in 62 out of 64 (97%) patients with PA. Only 4 out of 64 cases with PA (6.4%) ended the oral furosemide test with potassium <3.5 mEq/L. Hypotension was not evidenced in any patient with PA during the test. Conclusion: The oral furosemide test was safe, well-tolerated and represents an effective strategy for PA investigation.

Intra-individual Variability of Serum Aldosterone and Implications for Primary Aldosteronism Screening.

CONTEXT: Primary aldosteronism (PA) screening relies on an elevated aldosterone to renin ratio with a minimum aldosterone level, which varies from 10 to 15 ng/dL (277-415.5 pmol/L) using immunoassay. OBJECTIVE: To evaluate intra-individual coefficient of variation (CV) of aldosterone and aldosterone to direct renin concentration ratio (A/DRC) and its impact on PA screening. METHODS: A total of 671 aldosterone and DRC measurements were performed by the same chemiluminescence assays in a large cohort of 216 patients with confirmed PA and at least 2 screenings. RESULTS: The median intra-individual CV of aldosterone and A/DRC was 26.8% and 26.7%. Almost 40% of the patients had at least one aldosterone level <15 ng/dL, 19.9% had at least 2 aldosterone levels <15 ng/dL, and 16.2% had mean aldosterone levels <15 ng/dL. A lower cutoff of 10 ng/dL was associated with false negative rates for PA screening of 14.3% for a single aldosterone measurement, 4.6% for 2 aldosterone measurements, and only 2.3% for mean aldosterone levels. Considering the minimum aldosterone, true positive rate of aldosterone thresholds was 85.7% for 10 ng/dL and 61.6% for 15 ng/dL. An A/DRC >2 ng/dL/µIU/mL had a true positive rate for PA diagnosis of 94.4% and 98.4% when based on 1 or 2 assessments, respectively. CV of aldosterone and A/DRC were not affected by sex, use of interfering antihypertensive medications, PA lateralization, hypokalemia, age, and number of hormone measurements. CONCLUSION: Aldosterone concentrations had a high CV in PA patients, which results in an elevated rate of false negatives in a single screening for PA. Therefore, PA screening should be based on at least 2 screenings with concomitant aldosterone and renin measurements.

Directly observed therapy for resistant/refractory hypertension diagnosis and blood pressure control.

OBJECTIVE: To test the impact of directly observed therapy (DOT) at hospital for checking not only adherence/diagnosis in patients with resistant (RHTN) and refractory (RefHTN) hypertension but also blood pressure (BP) control after hospital discharge. METHODS: During 2 years, Brazilian patients with clinical suspicion of RHTN/RefHTN after several attempts (≥3) to control BP in the outpatient setting were invited to perform DOT (including low-sodium diet and supervised medications intake) at the hospital. RHTN and RefHTN were categorised using standard definitions. After hospital discharge, we evaluated the BP values and the number of antihypertensive drugs prescribed by physicians who were not involved with the investigation. RESULTS: We studied 83 patients clinically suspected for RHTN (31%) and RefHTN (69%) (mean age: 53 years; 76% female; systolic BP 177±28 mm Hg and diastolic BP 106±21 mm Hg; number of antihypertensive drugs: 5.3±1.3). DOT confirmed RHTN in 77%, whereas RefHTN was confirmed in only 32.5%. The number of antihypertensive drugs reduced to 4.5±1.3 and systolic/diastolic BP at hospital discharge reduced to 131±17 mm Hg/80±12 mm Hg. After hospital discharge, systolic BP remained significantly lower than the last outpatient visit prehospital admission (delta changes (95% CI): 1 month: -25.7 (-33.8 to -17.6) mm Hg; 7 months: -27.3 (-35.5 to -19.1) mm Hg) despite fewer number of antihypertensive classes (1 month: -1.01 (-1.36 to -0.67); 7 months: -0.77 (-1.11 to -0.42)). Similar reductions were observed for diastolic BP. CONCLUSIONS: DOT at hospital is helpful not only in confirming/excluding RHTN/RefHTN phenotypes, but also in improving BP values and BP control and in reducing the need for antihypertensive drugs after hospital discharge.

Evaluation of central venous catheter and other risk factors for mortality in chronic hemodialysis patients with COVID-19 in Brazil.

PURPOSE: Hemodialysis patients with COVID-19 are at increased risk of death. We aimed to describe the characteristics of a cohort of Brazilian hemodialysis patients with COVID-19 and assess their mortality rate and risk factors for death. METHODS: Retrospective cohort study of 741 Brazilian hemodialysis patients with confirmed COVID-19 from Feb-Dec/2020, of 52 dialysis centers of the country. We analyzed comorbid conditions, sociodemographic factors, and dialysis-related parameters. To detect risk factors for mortality in hemodialysis patients, we performed multivariable Cox proportional hazard regression analysis. Survival was analyzed by Kaplan-Meier. RESULTS: From 9877 hemodialysis patients, 741 were diagnosed with COVID-19. Mean age was 57 ± 16 years, 61% were male, and 51% white. The most frequent symptoms were fever (54.1%), cough (50.9%), and dyspnea (37.2%); 14.2% were asymptomatic. There were 139 deaths (18.8%), with 66% within the disease's first 15 days. 333 patients (44.9%) required hospitalization, and 211 (28.5%) were admitted to an intensive care unit. The cumulative probability of survival at 90 days of diagnosis was 79% (95% CI 76-82%). In the fully adjusted multivariate model, the risk factors significantly associated with death were diabetes mellitus (HR 1.52, 95% CI 1.05-2.19, P = 0.026), use of a central venous catheter (CVC) (HR 1.79, 95% CI 1.22-2.64, P = 0.003), age (HR 1.03, 95% CI 1.01-1.04, P < 0.001), and origin from the North vs. Southeast region (HR 2.60, 95% CI 1.01-6.68, P = 0.047). CONCLUSIONS: Hemodialysis patients using a CVC as the vascular access, aside from diabetic and elderly ones, should be closely monitored due to their high risk of death in the course of the COVID-19.

Obstructive sleep apnea and ambulatory blood pressure monitoring: current evidence and research gaps.

Obstructive Sleep Apnea (OSA) is a common condition characterized by intermittent collapse of the upper airway during sleep, resulting in partial (hypopnoeas) and total obstructions (apneas). These respiratory events observed in OSA may trigger multiple pathways involved in the blood pressure (BP) instability during the night and potentially influencing daytime BP as well (carry-over effects). This review provides an update about the impact of OSA and its treatments on 24-h BP control. Overall, there is growing evidence suggest that OSA is associated with higher frequency of nondipping BP pattern and nocturnal hypertension in a dose-dependent manner. The presence of nondiping BP (especially the reverse pattern) is independently associated with OSA regardless of sleep-related symptoms suggesting a potential tool for screening OSA in patients with clinical indication for performing ABPM. Beyond dipping BP, preliminary evidence associated OSA with white-coat effect and higher frequency of masked hypertension and BP variability than the control group (no OSA). Unfortunately, most of the evidence on the evidence addressing the impact of OSA treatment on BP was limited to office measurements. In the last years, data from observational and randomized studies pointed that CPAP is able to promote 24-h BP decrease especially in patients with resistant and refractory hypertension. A randomized trial suggests that CPAP is able to decrease the rate of masked hypertension as compared to no treatment in patients with severe OSA. Interestingly, nondipping BP is a good predictor of BP response to CPAP making ABPM an interesting tool for better OSA management.

Association of Sodium with Obstructive Sleep Apnea. The ELSA-Brasil Study.

Rationale: Excessive sodium may have a role in the pathogenesis of obstructive sleep apnea (OSA) for patients with hypervolemic conditions, but it is unclear whether this is valid for all patients with OSA, including those with no significant comorbidities.Objectives: To test the association of urinary sodium and OSA in a large sample of participants from the ELSA-Brasil (Estudo Longitudinal de Saúde do Adulto-Brasil) Study. In addition, we stratified the analysis participants according to the presence of hypertension.Methods: In this cross-sectional study, OSA was defined by an apnea-hypopnea index ≥15 events/h. A validated 12-hour urine collection as representative of the 24-hour period was obtained from all participants to measure sodium excretion. We performed a logistic regression analysis to test the association of urinary sodium excretion with OSA (dependent variable) adjusting for age, sex, race and income, glomerular filtration rate, diabetes, physical activity, and antihypertensive classes related to sodium excretion. To address potential residual factors that may influence sodium excretion, we performed additional analysis replacing sodium excretion for salt intake (food frequency questionnaire) using the same models.Results: We studied 1,946 participants (age 49 ± 8 yr; 43.4% men). A third of them had OSA. Compared with those with no OSA, participants with OSA presented with higher sodium excretion (1.66 [1.19-2.29] vs. 1.99 [1.44-2.69] g/12 h; P < 0.001). After adjustments for confounding factors, we found no overall significant associations of sodium excretion with OSA (odds ratio [OR], 1.09; 95% confidence interval [CI], 0.97-1.23; P = 0.150). Regardless of the OSA status, the sodium excretion was higher in hypertensive than in normotensive participants (1.93 [1.35-2.64] vs. 1.71 [1.22-2.37] g/12 h). An independent association of sodium excretion with OSA was observed in patients with hypertension only (OR, 1.326; 95% CI, 1.067-1.648; P = 0.011), but the interaction of urinary sodium with hypertension was not significant (P = 0.37). The analysis of salt intake revealed consistent findings.Conclusions: The potential role of sodium in the pathogenesis of OSA seems to be modest and limited for those with higher salt intake and, consequently, higher fluid retention such as observed in patients with hypertension.

Comparison of morning versus evening aerobic-exercise training on heart rate recovery in treated hypertensive men: a randomized controlled trial.

Heart rate recovery (HRR) is a marker of cardiac autonomic regulation and an independent predictor of mortality. Aerobic-exercise training conducted in the evening (evening training) produces greater improvement in resting cardiac autonomic control in hypertensives than morning training, suggesting it may also result in a faster autonomic restoration postexercise. This study compared the effects of morning training and evening training on HRR in treated hypertensive men. Forty-nine treated hypertensive men were randomly allocated into three groups: morning training, evening training and control. Training was conducted three times/week for 10 weeks. Training groups cycled (45 min, moderate intensity) while control group stretched (30 min). In the initial and final assessments of the study, HRR60s and HRR300s were evaluated during the active recovery (30 W) from cardiopulmonary exercise tests (CPET) conducted in the morning and evening. Between-within ANOVAs were applied (P ≤ 0.05). Only evening training increased HRR60s and HRR300 differently from control after morning CPET (+4 ± 5 and +7 ± 8 bpm, respectively, P < 0.05) and only evening training increased HRR300s differently from morning training and control after evening CPET (+8 ± 6 bpm, P < 0.05). Evening training improves HRR in treated hypertensive men, suggesting that this time of day is better for eliciting cardiac autonomic improvements via aerobic training in hypertensives.

The effect of continuous positive airway pressure on blood pressure in patients with obstructive sleep apnea and uncontrolled hypertension - Study design and challenges during the COVID-19 pandemic.

OBJECTIVES: To describe the MORPHEOS (Morbidity in patients with uncontrolled HTN and OSA) trial, and describe the challenges imposed by the COVID-19 pandemic. METHODS: MORPHEOS is a multicenter (n=6) randomized controlled trial designed to evaluate the blood pressure (BP) lowering effects of treatment with continuous positive airway pressure (CPAP) or placebo (nasal strips) for 6 months in adult patients with uncontrolled hypertension (HTN) and moderate-to-severe obstructive sleep apnea (OSA). Patients using at least one antihypertensive medication were included. Uncontrolled HTN was confirmed by at least one abnormal parameter in the 24-hour ABPM and ≥80% medication adherence evaluated by pill counting after the run-in period. OSA was defined by an apnea-hypopnea index ≥15 events/hours. The co-primary endpoints are brachial BP (office and ambulatory BP monitoring, ABPM) and central BP. Secondary outcomes include hypertension-mediated organ damage (HMOD) to heart, aorta, eye, and kidney. We pre-specified several sub-studies from this investigation. Visits occur once a week in the first month and once a month thereafter. The programmed sample size was 176 patients but the pandemic prevented this final target. A post-hoc power analysis will be calculated from the final sample. ClinicalTrials.gov: NCT02270658. RESULTS: The first 100 patients are predominantly males (n=69), age: 52±10 years, body mass index: 32.7±3.9 kg/m2 with frequent co-morbidities. CONCLUSIONS: The MORPHEOS trial has a unique study design including a run-in period; pill counting, and detailed analysis of hypertension-mediated organ damage in patients with uncontrolled HTN that will allow clarification of the impact of OSA treatment with CPAP.

KCNJ5 Somatic Mutation Is a Predictor of Hypertension Remission After Adrenalectomy for Unilateral Primary Aldosteronism.

CONTEXT: Primary aldosteronism (PA) is the most common cause of endocrine hypertension (HT). HT remission (defined as blood pressure <140/90 mm Hg without antihypertensive drugs) has been reported in approximately 50% of patients with unilateral PA after adrenalectomy. HT duration and severity are predictors of blood pressure response, but the prognostic role of somatic KCNJ5 mutations is unclear. OBJECTIVE: To determine clinical and molecular features associated with HT remission after adrenalectomy in patients with unilateral PA. METHODS: We retrospectively evaluated 100 patients with PA (60 women; median age at diagnosis 48 years with a median follow-up of 26 months). Anatomopathological analysis revealed 90 aldosterone-producing adenomas, 1 carcinoma, and 9 unilateral adrenal hyperplasias. All patients had biochemical cure after unilateral adrenalectomy. KCNJ5 gene was sequenced in 76 cases. RESULTS: KCNJ5 mutations were identified in 33 of 76 (43.4%) tumors: p.Gly151Arg (n = 17), p.Leu168Arg (n = 15), and p.Glu145Gln (n = 1). HT remission was reported in 37 of 100 (37%) patients. Among patients with HT remission, 73% were women (P = 0.04), 48.6% used more than three antihypertensive medications (P = 0.0001), and 64.9% had HT duration <10 years (P = 0.0015) compared with those without HT remission. Somatic KCNJ5 mutations were associated with female sex (P = 0.004), larger nodules (P = 0.001), and HT remission (P = 0.0001). In multivariate analysis, only a somatic KCNJ5 mutation was an independent predictor of HT remission after adrenalectomy (P = 0.004). CONCLUSION: The presence of a KCNJ5 somatic mutation is an independent predictor of HT remission after unilateral adrenalectomy in patients with unilateral PA.