Salidroside attenuates atrial fibrosis and atrial fibrillation vulnerability induced by angiotensin-II through inhibition of LOXL2-TGF-ß1-Smad2/3 pathway.

Aims and objectives: Salidroside (SAL), an active component isolated from the Chinese plant Rose Rhodiola, has anti-inflammatory, antioxidant, anti-cancer, neuroprotective, and renal protective properties. Atrial fibrosis developed due to angiotensin II (Ang II) plays a crucial function in developing atrial fibrillation (AF). This research investigates the involvement of SAL in AF, its vulnerability to AF, and Ang II-induced inflammatory atrial fibrosis. Methods: Ang II (2 mg/kg/day) was infused underneath the skin into male C57BL/6 mice (8-10 weeks old, n = 40) for four weeks to create the AF model. SAL (50 mg/kg/day) was given intraperitoneally once per day for 28 days. Analyses of morphology, histology, and biochemical were carried out. Transesophageal burst pacing was used in vivo to induce AF. Results: Ang II injection increased mice's heart rate and systolic blood pressure (SBP), whereas SAL treatment was significantly reduced. Ang II infusion increased left atrial diameter (LAD) in mice, which was attenuated after SAL treatment. SAL alone did not affect AF inducibility, but SAL therapy markedly decreased Ang II-induced AF inducibility. Additionally, the expression levels of interleukin-1 beta (IL-1ß), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) were inhibited with SAL therapy in mice. Compared to the Ang II group, Ang II infusion raised malondialdehyde (MDA) levels and reduced superoxide dismutase (SOD) and catalase (CAT) activity, but SAL therapy altered all of these effects. SAL treatment significantly reduced LOXL2, TGF-ß1, p-Smad2 and p-Smad3 protein expression than the Ang II group mice. Conclusion: SAL inhibits atrial fibrosis and potentially attenuates increased susceptibility to AF by suppressing the LOXL2-TGF-ß1-Smad2/3 pathway.

Stachydrine ameliorates hypoxia reoxygenation injury of cardiomyocyte via enhancing SIRT1-Nrf2 pathway.

BACKGROUND: Hypoxia/reoxygenation (H/R)-induced cardiomyocyte cell apoptosis is critical in developing myocardial infarction. Stachydrine (STA), an active constituent of Leonurus heterophyllus sweet, could have a protective effect on myocardial H/R injury, which remains unexplored. Therefore, the study aimed to investigate the protective effects and mechanisms of STA on H/R injury of cardiomyocytes. METHODS: Rat cardiomyocyte H9c2 cells underwent H/R (hypoxia for 4 h and reoxygenation for 12 h). Cells were pretreated with STA (50 µM) 2 h before H/R. Cardiomyocyte injury was evaluated by CCK-8 assay and lactate dehydrogenase (LDH) release. Apoptosis was assessed by TUNEL staining and caspase-3 activity. Oxidative stress was assessed by lipid oxidation product MDA and a ROS-scavenging enzyme SOD in culture media. Western blot was performed to measure the protein expressions of SIRT1, Nrf2, and heme oxygenase-1 (HO-1). RESULTS: STA reversed the decrease in cell viability and increased LDH release in H9c2 cells with the H/R insult. STA significantly suppressed oxidative stress, reduced MDA content, and increased SOD activity in H9c2 cells exposed to H/R. STA reduced apoptosis in H9c2 cells exposed to H/R, as evidenced by the reduced TUNEL positive cells and caspase-3 activity. In addition, STA enhanced SIRT1, Nrf2, and HO-1 protein expression in H/R-stimulated H9c2 cells. SIRT1 and Nrf2 involved the protective effect of STA in H/R-exposed H9c2 cells, as the changes in cell viability and caspase-3 activity by STA can be reversed by SIRT1 inhibitor EX-527 or Nrf2 siRNA. CONCLUSIONS: Our data speculated that STA protects H/R injury and inhibits oxidative stress and apoptosis in cardiomyocytes by activation of the SIRT1-Nrf2 pathway.

Irisin attenuates angiotensin II-induced atrial fibrillation and atrial fibrosis via LOXL2 and TGFß1/Smad2/3 signaling pathways.

Objectives: Irisin was reported as a cardioprotective and anti-oxidative effector, while the effect on atrial fibrosis is unknown. The current research examined irisin's function in atrial fibrillation (AF); atrial fibrosis brought on by Ang II can be suppressed, thus lessening the risk of developing AF. Materials and Methods: 246 individuals were enrolled in the present case-control study. Chinese AF patients (n=126), 83 of whom were paroxysmal AF (PAF), 43 patients with persistent AF (PeAF), and 120 healthy controls. Saline or Ang II (2.0 mg/kg/day) was subcutaneously injected into healthy male C57BL/6 mice for four weeks. Once daily for four weeks, intraperitoneal injections of exogenous irisin (500 g/kg/day) were administered. Results: In comparison to PAF patients and healthy controls (all P<0.05), PeAF patients had significantly higher rates of heart failure (HF), large left atrial size (LAD), hypertrophic protein B-type natriuretic peptide (BNP), malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), C-terminal telopeptide of type I collagen (CTX-I), and transforming growth factor beta-1 (TGF-ß1), while superoxide dismutase (SOD) level was low. Expression of irisin was decreased in AF patients' serum and Ang II-infused mice. Exogenous irisin dramatically reduced apoptosis, atrial fibrosis, atrial inflammation, and the susceptibility to AF caused by Ang II. In the atrial tissue, irisin inhibited Ang II-induced fibroblast transdifferentiation, LOXL2, TGF-ß1, collagen production, and phosphorylation of Smad2/3. Conclusion: The study results speculated that irisin could be a potential AF target, and it inhibited atrial fibrosis and significantly impaired increased AF susceptibility through inactivation of LOXL2 and the TGF-ß/Smad pathway.

Echinacoside ameliorates 5-fluorouracil-induced endothelial injury and senescence through SIRT1 activation.

Echinacoside (ECH) is a natural bioactive component with antioxidant, anti-inflammatory, anti-apoptosis, and anti-tumor properties. In the current study, we explore the ECH-mediated protective effect and underlying mechanism of 5-fluorouracil (5-FU)-induced endothelial injury and senescence in the Human umbilical vein endothelial cells (HUVECs). In HUVECs, Cell viability, Apoptosis and Senescence assays evaluated 5-fluorouracil-induced endothelial injury and senescence. Protein expressions were assessed using RT-qPCR and Western blotting. Our results showed that 5-FU-induced endothelial injury and endothelial cell senescence could be improved when treated with ECH in HUVECs. ECH treatment potentially attenuated oxidative stress and ROS production in HUVECs. In addition, the effect of ECH on autophagy markedly reduced the percentage of HUVECs with LC3-II dots and suppressed the Beclin-1 and ATG7 mRNA expression but enhanced the p62 mRNA expression. Besides, ECH treatment significantly increased migrated cells and suppressed the adhesion of THP-1 monocytes in HUVECs. Furthermore, ECH treatment activated the SIRT1 pathway, and its related proteins (SIRT1, p-AMPK and eNOS) expression increased. Nicotinamide (NAM), an inhibitor of SIRT1, significantly attenuated the ECH-induced decrease in the apoptotic rate, increased SA-ß-gal-positive cells and significantly reversed the ECH-induced reduction of endothelial senescence. Our results demonstrated that ECH employed endothelial injury and senescence in HUVECs via activation of the SIRT1 pathway.

BRD4 Silencing Protects Angiotensin II-Induced Cardiac Hypertrophy by Inhibiting TLR4/NF-κB and Activating Nrf2-HO-1 Pathways.

Background: Heart failure is a critical health problem worldwide, and cardiac hypertrophy is an important characteristic of heart failure. Bromodomain-containing protein 4 (BRD4) is involved in various cellular processes, including cardiac hypertrophy. This study aimed to investigate the mechanism underlying the effects of BRD4 on cardiac hypertrophy. Methods: Rat myoblast H9c2 cells were treated with angiotensin II (Ang II) to increase the mRNA and protein expressions of BRD4. BRD4 was silenced by small interfering RNA (siRNA) in H9c2 cells. Proteins involved in Nrf2-HO-1 pathway were determined by Western blot. Results: Our data suggest that BRD4 silencing attenuated Ang II, increased the percentage of TUNEL + cells and caspase-3 activity, increased oxidative stress, and increased the expression and content of pro-inflammatory cytokines. Mechanistically, we found that BRD4 silencing enhanced the protein expressions of Nrf2 and HO-1 and inhibited the TLR4 and phosphorylation of NF-kappa B in Ang II-stimulated H9c2 cells. TLR4 overexpression attenuated cardioprotection against Ang II by BRD4 silencing, including cardiac hypertrophy, oxidative stress, and inflammatory cytokine production. Additionally, TLR4 overexpression attenuated an increase in Nrf2 and HO-1 proteins and decreased phosphorylated NF-kappa B in H9c2 cells. Conclusion: Our results speculate that the BRD4/TLR4 axis might be a promising strategy for treating cardiovascular diseases with cardiac hypertrophy, including HF.

LOXL2 silencing suppresses angiotensin II-induced cardiac hypertrophy through the EMT process and TGF-ß1/Smad3/NF-κB pathway.

Objectives: Atrial fibrillation (AF) is a common arrhythmia with atrial myocyte hypertrophy linked with stroke, heart failure, and increased mortality. Lysyl oxidase-like 2 (LOXL2) involves the cross-linking of collagen in the extracellular matrix (ECM). In the present study, we investigated the roles and underlying mechanisms of LOXL2 on cardiomyocyte hypertrophy. Materials and Methods: The expression of LOXL2 mRNA and protein were detected in angiotensin II (Ang II) treated rat cardiomyocytes H9c2 by RT-qPCR and western blot. Small interfering RNA (siRNA) mediated LOXL2 gene silencing was used to evaluate cardiac hypertrophy and related markers. Also, the protein expression of EMT markers and Smad3/NF-κB pathway was determined by western blot. Results: Ang II significantly increased mRNA and protein expressions of LOXL2 and increased mRNA levels of myocardial hypertrophy markers, including ANP, BNP, and ß-MHC in H9c2 cells. Silencing of LOXL2 significantly suppressed Ang II-induced hypertrophy and reversed the increase in ANP, BNP, and ß-MHC mRNA levels. Also, EMT markers' expressions, as evidenced by increased E-cadherin and decreased vimentin, α-smooth muscle actin (α-SMA), fibroblast-specific protein (FSP), and collagen 1A1. Mechanistically, we found that LOXL2 silencing suppressed protein expressions of TGF-ß1, p-Smad3, and p-NF-κB in Ang II-stimulated H9c2 cells. LOXL2 silencing also attenuated Ang II-induced increased expression and content of proinflammatory cytokines IL-1ß (H) and TNF-α. Conclusion: Our data speculated that LOXL2 might be a potential contributing factor to Ang II-induced cardiac hypertrophy, and TGF-ß1/Smad3/NF-κB is involved in a signal axis and might be a potential strategy in treating cardiac hypertrophy.

LOXL2 Inhibitor Attenuates Angiotensin II-Induced Atrial Fibrosis and Vulnerability to Atrial Fibrillation through Inhibition of Transforming Growth Factor Beta-1 Smad2/3 Pathway.

OBJECTIVES: Angiotensin II (Ang II)-induced atrial fibrosis plays a vital role in the development of atrial fibrillation (AF). Lysyl oxidase-like 2 (LOXL2) plays an essential role in matrix remodeling and fibrogenesis, indicating it may involve fibrosis-associated diseases. This study aims to elucidate the role of LOXL2 in AF, and its specific inhibitor can suppress Ang II-induced inflammatory atrial fibrosis and attenuate the enhanced vulnerability to AF. METHODS: Male mice C57BL/6 were subcutaneously infused with either saline or Ang II (2 mg/kg/day) for 4 weeks. DMSO or LOXL2 inhibitor LOXL2-IN-1 hydrochloride (LOXL2-IN-1) at a dose of 100 µg/kg/day were intraperitoneally injected once daily for 4 weeks. Morphological, histological, and biochemical analyses were performed. AF was induced by transesophageal burst pacing in vivo. RESULTS: Expression of LOXL2 was increased in serum of AF patients and Ang II-treated mice. LOXL2-IN-1 significantly attenuated Ang II-induced AF vulnerability, cardiac hypertrophy, atrial inflammation, and fibrosis. LOXL2-IN-1 suppressed Ang II-induced expression of transforming growth factor beta-1 (TGF-ß1) and collagen I and phosphorylation of Smad2/3 in atrial tissue. CONCLUSIONS: LOXL2 is a target of AF, and its inhibitor prevents atrial fibrosis and attenuated enhanced vulnerability to AF potentially through the TGF-ß/Smad pathway.

Meta-Analysis of Catheter Ablation versus Medical Therapy for Heart Failure Complicated with Atrial Fibrillation.

OBJECTIVE: To compare the efficacy of catheter ablation and medical therapy in patients with heart failure and atrial fibrillation. METHODS: We searched randomized controlled trials comparing catheter ablation versus medical therapy for heart failure and atrial fibrillation through PubMed, MEDLINE, Embase, Cochrane Clinical Trials Database, Web of Science, and China National Knowledge Infrastructure. Articles were investigated for their methodological quality using the Cochrane Collaboration risk of the bias assessment tool. Forest plots, funnel plots, and sensitivity analysis were also performed on the included articles. Results were expressed as risk ratio (RR) and mean difference (MD) with 95% confidence intervals. RESULTS: Nine (9) studies were included in this study with 1131 patients. Meta-analysis showed a reduction in all-cause mortality from catheter ablation compared with medical therapy (RR = 0.53, 95% CI = 0.37 to 0.76; P=0.0007) and improved left ventricular ejection fraction (LVEF) (MD = 6.45, 95% CI = 3.49 to 9.41; P < 0.0001), 6-minute walking time (6MWT) (MD = 28.32, 95% CI = 17.77 to 38.87; P < 0.0001), and Minnesota Living with Heart Failure Questionnaire (MLHFQ) score (MD = 8.19, 95% CI = 0.30 to 16.08; P=0.04). CONCLUSION: Catheter ablation had a better improvement than medical treatment in left ventricular ejection fraction, cardiac function, and exercise ability for atrial fibrillation and heart failure patients.

Relationship between serum angiopoietin-like 4 levels and recurrence of atrial fibrillation.

OBJECTIVE: To investigate the association between serum angiopoietin-like 4 (ANGPTL4) levels and recurrence of atrial fibrillation (AF) after catheter ablation. METHODS: This retrospective study recruited patients with AF undergoing catheter ablation and they were divided into two groups (new-onset AF group and recurrent AF group). Demographic, clinical, and laboratory parameters were collected. RESULTS: A total of 192 patients with AF were included, including 69 patients with recurrence of AF. Serum ANGPTL4 levels were lower in patients with recurrent AF than in those with new-onset AF. Serum ANGPTL4 levels were positively correlated with superoxide dismutase and peroxisome proliferator-activated receptor γ, and negatively correlated with the CHA2DS2-VASC score, left atrial diameter, and levels of brain natriuretic peptide, malondialdehyde, high-sensitivity C-reactive protein, and interleukin-6. The receiver operating characteristic curve showed that the best cut-off for recurrent AF was serum ANGPTL4 levels < 19.735 ng/mL, with a sensitivity and specificity of 63.9% and 74.5%, respectively. Serum ANGPTL4 levels were significantly associated with recurrence and new onset of AF (odds ratio, 2.241; 95% confidence interval, 1.081-4.648). CONCLUSIONS: Serum ANGPTL4 levels are lower in patients with recurrent AF than in those with new-onset AF, and are associated with cardiac hypertrophy, oxidative stress, and inflammation.

miR-185 silencing promotes the progression of atherosclerosis via targeting stromal interaction molecule 1.

BACKGROUND: Atherosclerosis (AS) is a major risk factor for cardiovascular disease. microRNAs play a key role in gene regulation in the formation and development of atherosclerotic plaques. Herein, the role and target gene of miR-185 in AS were explored. MATERIALS AND METHODS: Cell viability, migration and invasion were examined by cell counting kit-8 (CCK-8) and transwell assay. The relative luciferase activity was measured by luciferase reporter assay. The levels of miR-185, STIM1, vascular endothelial growth factor (VEGF) and matrix metalloprotein-9 (MMP-9) were evaluated by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blot. RESULTS: The results revealed that ox-LDL decreased miR-185 expression, and enhanced STIM1 expression in MOVAS cells, as well promoted cell viability, migration and invasion. 3'-UTR of STIM1 contained miR-185 binding site according to the Targetscan. miR-185 silencing or STIM1 overexpression promoted the viability, migration and invasion of ox-LDL-induced MOVAS cells. miR-185 overexpression or STIM1 silencing had the opposite effect. Besides, miR-185 silencing up-regulated the levels of VEGF and MMP-9 in vitro, and increased the lesions of arterial wall tissues and STIM1 positive rate in vivo. However, STIM1 silencing reversed these effects. CONCLUSIONS: Sum up, STIM1 was a potential target gene of miR-185 in AS. Knockdown of miR-185 facilitated the progression of AS through enhancing cell proliferation, migration and invasion via targeting STIM1. The research provides a novel view of miR-185/STIM1 axis function in AS development, and this targeting method may prevent and treat AS.

Effects of Different Limb Remote Ischaemic Preconditioning on Ischaemia Reperfusion Injury in an Acute Left Anterior Descending Artery Occlusion Rat Model.

BACKGROUND: The aim is to compare effects of three different protocols of limb remote ischaemic preconditioning (LRIP) on ischaemia reperfusion injury in an acute left anterior descending artery (LAD) occlusion model rat. METHODS: Forty adult male Wistar rats were randomly assigned into four groups: group A, control; group B, LRIP in bilateral upper-limb (BUL) IP; group C, LRIP in bilateral lower-limb (BLL) IP; group D, LRIP in bilateral upper and lower limbs (ULL) IP. The 60min ligation and 180min reperfusion in LAD were applied to all rats. Limb remote ischaemic preconditioning was performed using 5min occlusion and 15min reperfusion (six cycles). Heart rate, blood pressure and electrogastrography (EGG) were recorded. Creatine kinase isoenzyme (CK-MB) level and infarct size were measured. RESULTS: Limb remote ischaemic preconditioning did not significantly affect heart rate, systolic blood pressure and arrhythmia score. However, LRIP significantly increased DBP value and decreased CK-MB levels and infarct size in group B, C, and D. Moreover, LRIP in ULL had a significantly better effect on reducing infarct size than LRIP in BUL and BLL. CONCLUSIONS: Limb remote ischaemic preconditioning at limbs could significantly reduce reperfusion injury in the heart. Moreover, LRIP in ULL indicated a better effect in reducing infarct size than LRIP in BUL and BLL.

MicroRNA-185 inhibits angiogenesis in human microvascular endothelial cells through targeting stromal interaction molecule 1.

Angiogenesis is a vital biological mechanism representing the adaptive response to a variety of pathological stimuli such as hypoxia. It is regulated by several pro-angiogenic and anti-angiogenic microRNAs. Studies have demonstrated an altered microRNA-185 (miR-185) expression in endothelial cells under hypoxic conditions; however, its role in angiogenesis has not been elucidated. We investigated the role of miR-185 in angiogenesis and found that miR-185 had an inhibitory effect on cell proliferation, migration, and tube formation. Stromal interaction molecule 1 (STIM1) appeared to be a direct target of miR-185 by computational prediction; this was confirmed by luciferase reporter assay. Silencing of the STIM1 gene was found to mimic miR-185-mediated inhibition of angiogenesis. STIM1 overexpression eliminated the anti-angiogenic effect of miR-185. Our study results suggest a direct interaction between miR-185 and STIM1 mRNA in microvascular endothelial cells. MicroRNA-185 acted as a negative regulator of angiogenesis in microvascular endothelial cells through downregulation of the STIM1 protein.

Multidetector Computed Tomography Angiography Combined with Intravascular Ultrasound for the Evaluation of Coronary Veins for Percutaneous Mitral Annulus Repair Using Transcoronary Sinus Devices.

BACKGROUND: Multidetector computed tomography angiography (MDCTA) can be used to evaluate the target location of transcoronary sinus devices. This study aimed to assess the accuracy of MDCTA in evaluating the target location of transcoronary sinus devices compared with intravascular ultrasound (IVUS). MATERIALS AND METHODS: Forty-two patients planned to undergo mitral valve repair (MVR) were prospectively enrolled at Zhoupu Hospital (China) including 15 with secondary mitral regurgitation (MR) grade ≥3. MDCTA was performed to measure the diameters of coronary sinus ostium (CSO) and proximal anterior interventricular vein (PAIV) and the distance between them. RESULTS: During MVR, these parameters were measured using IVUS before electrode insertion. There was a strong linear correlation between the diameter of CSO measured by MDCTA and IVUS (r = 0.967, P < 0.001), as well as for PAIV (r = 0.954, P < 0.001) and the distance between them (r = 0.986, P < 0.001). No significant differences were found between the results measured by MDCTA and IVUS. The patients with secondary MR grade ≥3 had significantly larger CSO and PAIV measured by IVUS (P = 0.003 and P = 0.017, respectively), as well as by MDCTA (P = 0.010 and P = 0.008, respectively). CONCLUSION: Dual-source MDCTA might allow the quantitative evaluation of the target location of transcoronary sinus devices with a good accuracy. It may be a good choice for guiding the selection of transcoronary sinus devices.

Body surface area as a key determinant of aortic root and arch dimensions in a population-based study.

The associations between the aortic dimensions (of the aortic sinus, aortic annulus and aortic arch) and physiological variables have not been established in the Chinese population. The present study examined the associations among physiological variables to determine the aortic root and arch dimensions echocardiographically. The diameters of the aortic sinus, annulus and arch were measured in 1,010 subjects via 2-D echocardiography with a 3.5-MHz transducer in a trans-thoracic position. The images of the aortic sinus and aortic annulus were obtained from a standard parasternal long-axis view. The maximum diameter of the valve orifice was measured at the end of systole. The aortic arch dimension was visualized in the long-axis using a suprasternal notch window and the maximum transverse diameter was measured. Epidata 3.0, Excel 2007 and SPSS version 17.0 were used to collect and analyze the data. A total of 1,010 subjects were enrolled. The mean age was 55.0±17.0 years (range of 18 to 90 years). The body surface area (BSA) was the best predictor of all the studied physiological variables and may be used to predict aortic sinus, annulus and arch dimensions independently (r=0.54, 0.37 and 0.39, respectively). Gender, blood pressure, age and BSA are significant predictors of the aortic dimensions. Of these, BSA was the best predictor.

Association between the rate of the morning surge in blood pressure and cardiovascular events and stroke.

BACKGROUND: The exaggerated surge in morning blood pressure (BP) that many patients experience upon awakening may be closely related to target organ damage and may be a predictor of cardiovascular complications. However, no previous studies have evaluated the rate of this surge independently of the evening period. It remains unclear whether the rate of increase experienced during the surge is a significant or independent determinant of cardiovascular events. METHODS: We randomly selected 340 ambulatory BP monitoring (ABPM) patients. All subjects without type 2 diabetes mellitus were divided into two groups: hypertensive group (n = 170) and normotensive group (n = 170). We analyzed ambulatory blood pressure recordings using a double logistic curve-fitting procedure to determine whether the magnitude of the surge in BP and heart rate (HR) in the morning is related to the level of BP in hypertensive individuals. We evaluated the association between the rate of the morning surge in systolic BP (SBP) and the incidence of myocardial infarction and stroke in normotensive and hypertensive subjects. RESULTS: Comparisons between hypertensive and normotensive subjects showed that the rates of the morning surges in SBP, mean BP (MBP), and diastolic BP (DBP) were greater in the hypertensive group (P < 0.05) than in the normotensive group. The rate of morning surge in BP was found to be correlated with the daytime SBP (r = 0.236, P < 0.01), the difference between the day and night plateau (r = 0.249, P < 0.01), and the night SBP (r = -0.160, P < 0.05), respectively. After controlling for age, sex, and mean systolic pressure within 24 hours (24 h SBP), the rate of morning surge in SBP was closely correlated with daytime SBP (r = 0.463, P < 0.001), night SBP (r = -0.173, P < 0.05), and the difference between the day and night plateau (r = 0.267, P < 0.001). Logistic regression analysis revealed that the rate of morning surge in SBP was an independent determinant of myocardial infarction (OR = 1.266, 95% CI = 1.153 - 1.389, P < 0.001) and stroke (OR = 1.367, 95% CI = 1.174 - 1.591, P < 0.001). CONCLUSIONS: The rate of the morning surge in BP is greater in hypertensive subjects than in normotensive subjects. Daytime SBP may be the best predictor of the rate of morning surge in SBP. The rate of the morning surge in BP is associated with cardiovascular and stroke events.