Association Between Achieved Low-Density Lipoprotein Cholesterol Levels and Long-Term Cardiovascular and Safety Outcomes: An Analysis of FOURIER-OLE.

BACKGROUND: Low-density lipoprotein cholesterol (LDL-C) is a well-established risk factor for atherosclerotic cardiovascular disease. However, the optimal achieved LDL-C level with regard to efficacy and safety in the long term remains unknown. METHODS: In FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk), 27 564 patients with stable atherosclerotic cardiovascular disease were randomized to evolocumab versus placebo, with a median follow-up of 2.2 years. In the open-label extension (FOURIER-OLE), 6635 of these patients were transitioned to open-label evolocumab regardless of initial treatment allocation in the parent trial and were followed for an additional median of 5 years. In this prespecified analysis, we examined the relationship between achieved LDL-C levels (an average of the first 2 LDL-C levels measured) in FOURIER-OLE (available in 6559 patients) and the incidence of subsequent cardiovascular and safety outcomes. We also performed sensitivity analyses evaluating cardiovascular and safety outcomes in the entire FOURIER and FOURIER-OLE patient population. Multivariable modeling was used to adjust for baseline factors associated with achieved LDL-C levels. RESULTS: In FOURIER-OLE, 1604 (24%), 2627 (40%), 1031 (16%), 486 (7%), and 811 (12%) patients achieved LDL-C levels of <20, 20 to <40, 40 to <55, 55 to <70, and ≥70 mg/dL, respectively. There was a monotonic relationship between lower achieved LDL-C levels-down to very low levels <20 mg/dL-and a lower risk of the primary efficacy end point (composite of cardiovascular death, myocardial infarction, stroke, hospital admission for unstable angina or coronary revascularization) and the key secondary efficacy end point (composite of cardiovascular death, myocardial infarction, or stroke) that persisted after multivariable adjustment (adjusted Ptrend<0.0001 for each end points). No statistically significant associations existed in the primary analyses between lower achieved LDL-C levels and increased risk of the safety outcomes (serious adverse events, new or recurrent cancer, cataract-related adverse events, hemorrhagic stroke, new-onset diabetes, neurocognitive adverse events, muscle-related events, or noncardiovascular death). Similar findings were noted in the entire FOURIER and FOURIER-OLE cohort up to a maximum follow-up of 8.6 years. CONCLUSIONS: In patients with atherosclerotic cardiovascular disease, long-term achievement of lower LDL-C levels, down to <20 mg/dL (<0.5 mmol/L), was associated with a lower risk of cardiovascular outcomes with no significant safety concerns. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01764633.

Management of patients with hypertension and chronic kidney disease referred to Hypertension Excellence Centres among 27 countries. On behalf of the European Society of Hypertension Working Group on Hypertension and the Kidney.

Objective Real-life management of patients with hypertension and chronic kidney disease (CKD) among European Society of Hypertension Excellence Centres (ESH-ECs) is unclear : we aimed to investigate it. Methods A survey was conducted in 2023. The questionnaire contained 64 questions asking ESH-ECs representatives to estimate how patients with CKD are managed. Results Overall, 88 ESH-ECS representatives from 27 countries participated. According to the responders, renin-angiotensin system (RAS) blockers, calcium-channel blockers and thiazides were often added when these medications were lacking in CKD patients, but physicians were more prone to initiate RAS blockers (90% [interquartile range: 70-95%]) than MRA (20% [10-30%]), SGLT2i (30% [20-50%]) or (GLP1-RA (10% [5-15%]). Despite treatment optimisation, 30% of responders indicated that hypertension remained uncontrolled (30% (15-40%) vs 18% [10%-25%]) in CKD and CKD patients, respectively). Hyperkalemia was the most frequent barrier to initiate RAS blockers, and dosage reduction was considered in 45% of responders when kalaemia was 5.5-5.9 mmol/L. Conclusions RAS blockers are initiated in most ESH-ECS in CKD patients, but MRA and SGLT2i initiations are less frequent. Hyperkalemia was the main barrier for initiation or adequate dosing of RAS blockade, and RAS blockers' dosage reduction was the usual management.

What is the context? Hypertension is a strong independent risk factor for development of chronic kidney disease (CKD) and progression of CKD to ESKD. Improved adherence to the guidelines in the treatment of CKD is believed to provide further reduction of cardiorenal events. European Society of Hypertension Excellence Centres (ESH-ECs) have been developed in Europe to provide excellency regarding management of patients with hypertension and implement guidelines. Numerous deficits regarding general practitioner CKD screening, use of nephroprotective drugs and referral to nephrologists prior to referral to ESH-ECs have been reported. In contrast, real-life management of these patients among ESH-ECs is unknown. Before implementation of strategies to improve guideline adherence in Europe, we aimed to investigate how patients with CKD are managed among the ESH-ECs.What is the study about? In this study, a survey was conducted in 2023 by the ESH to assess management of CKD patients referred to ESH-ECs. The questionnaire contained 64 questions asking ESH-ECs representatives to estimate how patients with CKD are managed among their centres.What are the results? RAAS blockers are initiated in 90% of ESH-ECs in CKD patients, but the initiation of MRA and SGLT2i is less frequently done. Hyperkalemia is the main barrier for initiation or adequate dosing of RAAS blockade, and its most reported management was RAAS blockers dosage reduction. These findings will be crucial to implement strategies in order to improve management of patients with CKD and guideline adherence among ESH-ECs.

The Role of Opioid Receptor Antagonists in Regulation of Blood Pressure and T-Cell Activation in Mice Selected for High Analgesia Induced by Swim Stress.

Opioid peptides and their G protein-coupled receptors are important regulators within the cardiovascular system, implicated in the modulation of both heart and vascular functions. It is known that naloxone-an opioid antagonist-may exert a hypertensive effect. Recent experimental and clinical evidence supports the important role of inflammatory mechanisms in hypertension. Since opioids may play a role in the regulation of both blood pressure and immune response, we studied these two processes in our model. We aimed to evaluate the effect of selective and non-selective opioid receptor antagonists on blood pressure and T-cell activation in a mouse model of high swim stress-induced analgesia. Blood pressure was measured before and during the infusion of opioid receptor antagonists using a non-invasive tail-cuff measurement system. To assess the activation of T-cells, flow cytometry was used. We discovered that the non-selective antagonism of the opioid system by naloxone caused a significant elevation of blood pressure. The selective antagonism of µ and κ but not δ opioid receptors significantly increased systolic blood pressure. Subsequently, a brief characterization of T-cell subsets was performed. We found that the blockade of µ and δ receptors is associated with the increased expression of CD69 on CD4 T-cells. Moreover, we observed an increase in the central memory CD4 and central memory CD8 T-cell populations after the δ opioid receptor blockade. The antagonism of the µ opioid receptor increased the CD8 effector and central memory T-cell populations.

Mouse CCL9 Chemokine Acts as Tumor Suppressor in a Murine Model of Colon Cancer.

Colorectal cancer is the third most frequently diagnosed cancer in the world. Despite extensive studies and apparent progress in modern strategies for disease control, the treatment options are still not sufficient and effective, mostly due to frequently encountered resistance to immunotherapy of colon cancer patients in common clinical practice. In our study, we aimed to uncover the CCL9 chemokine action employing the murine model of colon cancer to seek new, potential molecular targets that could be promising in the development of colon cancer therapy. Mouse CT26.CL25 colon cancer cell line was used for introducing lentivirus-mediated CCL9 overexpression. The blank control cell line contained an empty vector, while the cell line marked as CCL9+ carried the CCL9-overexpressing vector. Next, cancer cells with empty vector (control) or CCL9-overexpressing cells were injected subcutaneously, and the growing tumors were measured within 2 weeks. Surprisingly, CCL9 contributed to a decline in tumor growth in vivo but had no effect on CT26.CL25 cell proliferation or migration in vitro. Microarray analysis of the collected tumor tissues revealed upregulation of the immune system-related genes in the CCL9 group. Obtained results suggest that CCL9 reveals its anti-proliferative functions by interplay with host immune cells and mediators that were absent in the isolated, in vitro system. Under specific study conditions, we determined unknown features of the murine CCL9 that have so far bee reported to be predominantly pro-oncogenic.

A new threshold for kidney asymmetry improves association with abnormal renal-aortic ratio for diagnosis of renal artery stenosis.

BACKGROUND: Renal artery stenosis (RAS) reflects more widespread atherosclerosis deposition and is associated with high morbidity and mortality. According to the guidelines, a discrepancy in the size of the kidneys of over 15 mm found in an ultrasound should initiate the RAS diagnostic algorithm. This study aims to find the optimal threshold for renal asymmetry that better reflects the frequency of a significantly abnormal renal-aortic ratio (RAR), justifying further RAS diagnostic workup, than the currently used cut-off of 15 mm difference in renal diameters. METHODS: The analysis included 1175 patients (mean age: 52 years, IQR: 38-66, men/women: 597/578) who underwent Doppler ultrasonography screening of renal arteries with recorded kidney size and RAR calculation. Ultrasound features of RAS were defined as a RAR greater than 3.5 or signs of renal artery occlusion. Receiver operating characteristic (ROC) curves were created and analyzed for absolute differences in kidney size and abnormal RAR. We calculated the area under the curve (AUC) and optimal cut-off values for sensitivity and specificity analysis. RESULTS: The final analysis included 169 patients with a significant difference in renal dimension. RAS features were met in 61 patients. According to ROC curve analysis, the optimal index of renal asymmetry was 12 mm. The sensitivity and specificity for this method were 82.0% and 83.3%, respectively, and AUC was 86.3%. CONCLUSION: Changing the definition of a significant difference in kidney size from 15 mm to 12 mm increases sensitivity and specificity for abnormal RAR and this finding may accelerate the diagnosis of RAS.

Cardiovascular Effects Mediated by HMMR and CD44.

Cardiovascular disease (CVD) is the leading cause of death worldwide. The most dangerous life-threatening symptoms of CVD are myocardial infarction and stroke. The causes of CVD are not entirely clear, and new therapeutic targets are still being sought. One of the factors involved in CVD development among vascular damage and oxidative stress is chronic inflammation. It is known that hyaluronic acid plays an important role in inflammation and is regulated by numerous stimuli, including proinflammatory cytokines. The main receptors for hyaluronic acid are CD44 and RHAMM. These receptors are membrane proteins that differ in structure, but it seems that they can perform similar or synergistic functions in many diseases. Both RHAMM and CD44 are involved in cell migration and wound healing. However, their close association with CVD is not fully understood. In this review, we describe the role of both receptors in CVD.

Hypertensive Effect of Downregulation of the Opioid System in Mouse Model of Different Activity of the Endogenous Opioid System.

The opioid system is well-known for its role in modulating nociception and addiction development. However, there are premises that the endogenous opioid system may also affect blood pressure. The main goal of the present study was to determine the impact of different endogenous opioid system activity and its pharmacological blockade on blood pressure. Moreover, we examined the vascular function in hyper- and hypoactive states of the opioid system and its pharmacological modification. In our study, we used two mouse lines which are divergently bred for high (HA) and low (LA) swim stress-induced analgesia. The obtained results indicated that individuals with low endogenous opioid system activity have higher basal blood pressure compared to those with a hyperactive opioid system. Additionally, naloxone administration only resulted in the elevation of blood pressure in HA mice. We also showed that the hypoactive opioid system contributes to impaired vascular relaxation independent of endothelium, which corresponded with decreased guanylyl cyclase levels in the aorta. Together, these data suggest that higher basal blood pressure in LA mice is a result of disturbed mechanisms in vascular relaxation in smooth muscle cells. We believe that a novel mechanism which involves endogenous opioid system activity in the regulation of blood pressure will be a promising target for further studies in hypertension development.

Effect of Chemokine (C-C Motif) Ligand 7 (CCL7) and Its Receptor (CCR2) Expression on Colorectal Cancer Behaviors.

Colorectal cancer is the source of one of the most common cancer-related deaths worldwide, where the main cause of patient mortality remains metastasis. The aim of this study was to determine the role of CCL7 (chemokine (C-C motif) ligand 7) in tumor progression and finding whether it could predict survival of colorectal cancer patients. Initially, our study focused on the crosstalk between mesenchymal stem cells (MSCs) and CT26 colon carcinoma cells and resulted in identifying CCL7 as a chemokine upregulated in CT26 colon cancer cells cocultured with MSCs, compared with CT26 in monoculture in vitro. Moreover, we showed that MSCs enhance CT26 tumor cell proliferation and migration. We analyzed the effect of CCL7 overexpression on tumor progression in a murine CT26 model, where cells overexpressing CCL7 accelerated the early phase of tumor growth and caused higher lung metastasis rates compared with control mice. Microarray analysis revealed that tumors overexpressing CCL7 had lower expression of immunoglobulins produced by B lymphocytes. Additionally, using Jh mutant mice, we confirmed that in the CT26 model, CCL7 has an immunoglobulin-, and thereby, B-cell-dependent effect on metastasis formation. Finally, higher expression of CCL7 receptor CCR2 (C-C chemokine receptor type 2) was associated with shorter overall survival of colorectal cancer patients. Altogether, we showed that CCL7 is essentially involved in the progression of colorectal cancer in a CT26 mouse model and that the expression of its receptor CCR2 could be related to a different outcome pattern of patients with colorectal carcinoma.

Red-cell distribution width is associated with higher risk of vascular complications after carotid thromboendartherectomy.

Red Cell Distribution Width (RDW) is associated with increased morbidity and mortality in subjects with clinically manifested vascular diseases as well as predicts cardiovascular incidents and different types of cancer in a healthy population. AIM: The aim of the study was to evaluate relationship between clinical outcomes in patients after carotid thromboendarterectomy and initial RDW values. MATERIALS AND METHODS: Data from 115 subsequent patients who underwent carotid thromboendartherectomy (TEA) were retrospectively analyzed. All patients had complete blood count measured including RDW and were observed for 18 months post-operatively. On each visit doppler ultrasound of carotid arteries was performed to evaluate the development of restenosis and progression of atherosclerosis. RESULTS: Primary endpoint defined as cardiovascular death, new cerebrovascular incidents (stroke or TIA), any new revascularization procedure (carotid, coronary or peripheral) and restenosis of the operated artery occurred in 28 patients. They differed from subjects with uneventful course with increased prevalence of previous cerebrovascular incidents (75.0% and 42.5%, respectively; p=0.0028) and higher RDW values (14,37±1.55% and 13.77±0.96%, p=0.0155). CONCLUSIONS: In patients with high risk for cerebrovascular incidents, RDW identifies population at increasingly high probability of vascular complications which should be subjected to intensive therapeutic regimen.

Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial.

BACKGROUND: LDL cholesterol is a well established risk factor for atherosclerotic cardiovascular disease. How much one should or safely can lower this risk factor remains debated. We aimed to explore the relationship between progressively lower LDL-cholesterol concentrations achieved at 4 weeks and clinical efficacy and safety in the FOURIER trial of evolocumab, a monoclonal antibody to proprotein convertase subtilisin-kexin type 9 (PCSK9). METHODS: In this prespecified secondary analysis of 25 982 patients from the randomised FOURIER trial, the relationship between achieved LDL-cholesterol concentration at 4 weeks and subsequent cardiovascular outcomes (primary endpoint was the composite of cardiovascular death, myocardial infarction, stroke, coronary revascularisation, or unstable angina; key secondary endpoint was the composite of cardiovascular death, myocardial infarction, or stroke) and ten prespecified safety events of interest was examined over a median of 2·2 years of follow-up. We used multivariable modelling to adjust for baseline factors associated with achieved LDL cholesterol. This trial is registered with ClinicalTrials.gov, number NCT01764633. FINDINGS: Between Feb 8, 2013, and June 5, 2015, 27 564 patients were randomly assigned a treatment in the FOURIER study. 1025 (4%) patients did not have an LDL cholesterol measured at 4 weeks and 557 (2%) had already had a primary endpoint event or one of the ten prespecified safety events before the week-4 visit. From the remaining 25 982 patients (94% of those randomly assigned) 13 013 were assigned evolocumab and 12 969 were assigned placebo. 2669 (10%) of 25 982 patients achieved LDL-cholesterol concentrations of less than 0·5 mmol/L, 8003 (31%) patients achieved concentrations between 0·5 and less than 1·3 mmol/L, 3444 (13%) patients achieved concentrations between 1·3 and less than 1·8 mmol/L, 7471 (29%) patients achieved concentrations between 1·8 to less than 2·6 mmol/L, and 4395 (17%) patients achieved concentrations of 2·6 mmol/L or higher. There was a highly significant monotonic relationship between low LDL-cholesterol concentrations and lower risk of the primary and secondary efficacy composite endpoints extending to the bottom first percentile (LDL-cholesterol concentrations of less than 0·2 mmol/L; p=0·0012 for the primary endpoint, p=0·0001 for the secondary endpoint). Conversely, no significant association was observed between achieved LDL cholesterol and safety outcomes, either for all serious adverse events or any of the other nine prespecified safety events. INTERPRETATION: There was a monotonic relationship between achieved LDL cholesterol and major cardiovascular outcomes down to LDL-cholesterol concentrations of less than 0·2 mmol/L. Conversely, there were no safety concerns with very low LDL-cholesterol concentrations over a median of 2·2 years. These data support further LDL-cholesterol lowering in patients with cardiovascular disease to well below current recommendations. FUNDING: Amgen.

The effect of statins on sympathetic activity: a meta-analysis.

OBJECTIVE: Beyond lipid-lowering properties, statins decrease sympathetic nervous activity. Due to the limited number of studies and included participants, a meta-analysis of randomized, placebo-controlled studies using microneurography (MSNA) was performed to assess sympatholytic effect of statins. METHODS: We conducted a comprehensive search of online databases (Cochrane, Embase, and EBSCO) for published human studies up to April 2014. Randomized controlled trials (parallel and crossover design) were eligible for inclusion if results of statins versus placebo treatments on sympathetic activity were measured with MSNA. RESULTS: Data from five studies with a total number of subjects n = 82 were included into the meta-analysis. MSNA expressed as bursts/min and as bursts/100 heartbeats was lower in the statin group than in the placebo group with a mean difference of -4.37 95% CI (-7.03; -1.70), p < 0.0013 and -5.85 95% CI (-7.56; -4.13), p < 0.0001, respectively. No significant publication bias was observed. Meta-regression revealed no significant effect of baseline total cholesterol or dose of statin. No change in blood pressure and heart rate was observed. CONCLUSIONS: Published data show that regardless of type and dose, statins reduce sympathetic activity measured by microneurography. The role of decreased sympathetic outflow during statin therapy on clinical end points needs to be clarified.

Does the control of negative emotions influence blood pressure control and its variability?

The aim was to assess the control of negative emotions in treated patients with hypertension in comparison with normotensive individuals and to evaluate the association between suppression of negative emotions, control of blood pressure (BP) on ambulatory blood pressure monitoring (ABPM) and blood pressure variability (BPV). We studied 195 patients (women/men: 89/106); mean age 45.4 ± 15.9 years. All patients had ABPM and completed the Courtauld Emotional Control Scale (CECS). The total CECS score and scores for subscales for anger, depression and anxiety were analyzed together with mean BP values from ABPM, and their SD and coefficient of variation as BPV measures. The mean CECS score was 54 ± 12 in all subjects; highest in uncontrolled hypertension 56 ± 11, intermediate 53 ± 12 in controlled hypertension and lowest 48 ± 12 in normotensive subjects. The reference value for the Polish population is 50 ± 11. Significant differences of mean CECS scores among groups were observed (p = 0.0165) also in multivariate analysis. The difference between uncontrolled hypertension and normotension was significant (p = 0.0262). Few significant, weak correlations were observed between CECS score or its subscales and ABPM derivates in all subjects. Conclusion. Suppression of negative emotions may adversely affect BP control in treated hypertensive patients and it should be considered a cause of uncontrolled hypertension.

Screening and management of hypertensive patients with chronic kidney disease referred to Hypertension Excellence Centres among 27 countries. A pilot survey based on questionnaire.

OBJECTIVE: Real-life management of hypertensive patients with chronic kidney disease (CKD) is unclear. METHODS: A survey was conducted in 2023 by the European Society of Hypertension (ESH) to assess management of CKD patients referred to ESH-Hypertension Excellence Centres (ESH-ECs) at first referral visit. The questionnaire contained 64 questions with which ESH-ECs representatives were asked to estimate preexisting CKD management quality. RESULTS: Overall, 88 ESH-ECs from 27 countries participated (fully completed surveys: 66/88 [75.0%]). ESH-ECs reported that 28% (median, interquartile range: 15-50%) had preexisting CKD, with 10% of them (5-30%) previously referred to a nephrologist, while 30% (15-40%) had resistant hypertension. The reported rate of previous recent (<6 months) estimated glomerular filtration rate (eGFR) and urine albumin-creatinine ratio (UACR) testing were 80% (50-95%) and 30% (15-50%), respectively. The reported use of renin-angiotensin system blockers was 80% (70-90%). When a nephrologist was part of the ESH-EC teams the reported rates SGLT2 inhibitors (27.5% [20-40%] vs. 15% [10-25], P = 0.003), GLP1-RA (10% [10-20%] vs. 5% [5-10%], P = 0.003) and mineralocorticoid receptor antagonists (20% [10-30%] vs. 15% [10-20%], P = 0.05) use were greater as compared to ESH-ECs without nephrologist participation. The rate of reported resistant hypertension, recent eGFR and UACR results and management of CKD patients prior to referral varied widely across countries. CONCLUSIONS: Our estimation indicates deficits regarding CKD screening, use of nephroprotective drugs and referral to nephrologists before referral to ESH-ECs but results varied widely across countries. This information can be used to build specific programs to improve care in hypertensives with CKD.

Effect of nateglinide on the incidence of diabetes and cardiovascular events.

BACKGROUND: The ability of short-acting insulin secretagogues to reduce the risk of diabetes or cardiovascular events in people with impaired glucose tolerance is unknown. METHODS: In a double-blind, randomized clinical trial, we assigned 9306 participants with impaired glucose tolerance and either cardiovascular disease or cardiovascular risk factors to receive nateglinide (up to 60 mg three times daily) or placebo, in a 2-by-2 factorial design with valsartan or placebo, in addition to participation in a lifestyle modification program. We followed the participants for a median of 5.0 years for incident diabetes (and a median of 6.5 years for vital status). We evaluated the effect of nateglinide on the occurrence of three coprimary outcomes: the development of diabetes; a core cardiovascular outcome that was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure; and an extended cardiovascular outcome that was a composite of the individual components of the core composite cardiovascular outcome, hospitalization for unstable angina, or arterial revascularization. RESULTS: After adjustment for multiple testing, nateglinide, as compared with placebo, did not significantly reduce the cumulative incidence of diabetes (36% and 34%, respectively; hazard ratio, 1.07; 95% confidence interval [CI], 1.00 to 1.15; P=0.05), the core composite cardiovascular outcome (7.9% and 8.3%, respectively; hazard ratio, 0.94, 95% CI, 0.82 to 1.09; P=0.43), or the extended composite cardiovascular outcome (14.2% and 15.2%, respectively; hazard ratio, 0.93, 95% CI, 0.83 to 1.03; P=0.16). Nateglinide did, however, increase the risk of hypoglycemia. CONCLUSIONS: Among persons with impaired glucose tolerance and established cardiovascular disease or cardiovascular risk factors, assignment to nateglinide for 5 years did not reduce the incidence of diabetes or the coprimary composite cardiovascular outcomes. (ClinicalTrials.gov number, NCT00097786.)

Effect of valsartan on the incidence of diabetes and cardiovascular events.

BACKGROUND: It is not known whether drugs that block the renin-angiotensin system reduce the risk of diabetes and cardiovascular events in patients with impaired glucose tolerance. METHODS: In this double-blind, randomized clinical trial with a 2-by-2 factorial design, we assigned 9306 patients with impaired glucose tolerance and established cardiovascular disease or cardiovascular risk factors to receive valsartan (up to 160 mg daily) or placebo (and nateglinide or placebo) in addition to lifestyle modification. We then followed the patients for a median of 5.0 years for the development of diabetes (6.5 years for vital status). We studied the effects of valsartan on the occurrence of three coprimary outcomes: the development of diabetes; an extended composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, arterial revascularization, or hospitalization for unstable angina; and a core composite outcome that excluded unstable angina and revascularization. RESULTS: The cumulative incidence of diabetes was 33.1% in the valsartan group, as compared with 36.8% in the placebo group (hazard ratio in the valsartan group, 0.86; 95% confidence interval [CI], 0.80 to 0.92; P<0.001). Valsartan, as compared with placebo, did not significantly reduce the incidence of either the extended cardiovascular outcome (14.5% vs. 14.8%; hazard ratio, 0.96; 95% CI, 0.86 to 1.07; P=0.43) or the core cardiovascular outcome (8.1% vs. 8.1%; hazard ratio, 0.99; 95% CI, 0.86 to 1.14; P=0.85). CONCLUSIONS: Among patients with impaired glucose tolerance and cardiovascular disease or risk factors, the use of valsartan for 5 years, along with lifestyle modification, led to a relative reduction of 14% in the incidence of diabetes but did not reduce the rate of cardiovascular events. (ClinicalTrials.gov number, NCT00097786.)

Blood pressure control and primary prevention of stroke: summary of the recent clinical trial data and meta-analyses.

Stroke is the second most common cause of death worldwide and of adult disability, but in the near future the global burden of cerebrovascular diseases will rise due to ageing and adverse lifestyle changes in populations worldwide. The risk of stroke increases at blood pressure levels above 115/75 mm Hg and high blood pressure (BP) is the most important modifiable risk factor for stroke, associated with 54 % episodes of stroke worldwide. There is strong evidence from clinical trials that antihypertensive therapy reduces substantially the risk of any type of stroke, as well as stroke-related death and disability. The risk attributed to BP is associated not only with absolute values but also with certain parameters describing BP diurnal pattern as well as short-term and long-term variability. Many studies reported that certain features of BP like nocturnal hypertension, morning surge or increased variability predict an increased stroke risk. However, there is no accepted effective modality for correction of these disturbances (chronotherapy, certain classes of antihypertensive drugs). In the elderly, who are mostly affected by stroke, the primary prevention guidelines recommend treatment with diuretics and calcium channel blockers to lower blood pressure to the standard level.

Lack of PTEN sequesters CHK1 and initiates genetic instability.

Pten-/- cells display a partially defective checkpoint in response to ionizing radiation (IR). The checkpoint defect was traced to the ability of AKT to phosphorylate CHK1 at serine 280, since a nonphosphorylated mutant of CHK1 (S280A) complemented the checkpoint defect and restored CDC25A degradation. CHK1 phosphorylation at serine 280 led to covalent binding of 1 to 2 molecules of ubiquitin and cytoplasmic CHK1 localization. Primary breast carcinomas lacking PTEN expression and having elevated AKT phosphorylation had increased cytoplasmic CHK1 and displayed aneuploidy (p <0.005). We conclude that loss of PTEN and subsequent activation of AKT impair CHK1 through phosphorylation, ubiquitination, and reduced nuclear localization to promote genomic instability in tumor cells.

Efficacy and safety of bisoprolol 5 mg plus amlodipine 5 mg in patients with hypertension uncontrolled on monotherapy with 5 mg of amlodipine, a phase III multicenter, randomized, double-blind, placebo-controlled clinical trial - the AMCOR study.

OBJECTIVE: To evaluate the antihypertensive effect and safety of bisoprolol 5 mg (BISO5mg) and amlodipine 5 mg (AMLO5mg) combination in comparison to AMLO5mg in hypertensive subjects uncontrolled with AMLO5mg. METHODS: Phase III, prospective, randomized, double-blind, placebo-controlled, 8-week trial with parallel design (EudraCT Number: 2019-000751-13). RESULTS: 367 patients aged 57.58 ± 14.62 years were randomized to BISO5mg once daily on top of AMLO5mg (n = 181) or placebo on top of AMLO5mg (n = 186). Systolic/diastolic blood pressure (SBP/DBP) in the bisoprolol-treated group was reduced by 7.2 ± 12.74/3.95 ± 8.85 mmHg at 4 weeks (both p < .0001) and by 5.5 ± 12.44/3.84 ± 9.46 mmHg at 8 weeks (p < .0001/p < .0002) compared to placebo control. Bisoprolol-treated group had lower heart rate than placebo control (difference -7.23 ± 9.84/-6.25 ± 9.26 beats per minute at 4 and 8 weeks, respectively, both p < .0001). Both target SBP and DBP was achieved at 4 weeks by 62 vs. 41% (p = .0002) and at 8 weeks by 65 vs. 46% (p = .0004) of bisoprolol-treated patients and placebo group patients, respectively. SBP <140 mmHg was achieved at 4 and 8 weeks in 68 and 69% of bisoprolol-treated patients and 45 and 50% of placebo group patients, respectively. No deaths and serious adverse events were reported. Adverse events occurred in 34 bisoprolol-treated patients vs. 22 patients in the placebo group (p = .064). Bisoprolol was withdrawn due to adverse events in 7 patients, mostly (n = 4) due to asymptomatic bradycardia. CONCLUSIONS: Addition of bisoprolol to patients uncontrolled with amlodipine monotherapy significantly improves blood pressure control. We can expect additional 7.2/3.95 mmHg SBP/DBP lowering effect by adding bisoprolol 5 mg to amlodipine 5 mg.

Preference and Adherence to a Fixed-Dose Combination of Bisoprolol-Aspirin and Blood Pressure Control: Results of an Open-Label, Multicentre Study.

This study assessed blood pressure (BP) control and adherence in patients given a fixed-dose combination (FDC) of bisoprolol (BIS) + aspirin (ASA) compared to those given these two drugs as separate tablets. Patients with hypertension and/or coronary heart disease treated with two-pill BIS (5−10 mg) and ASA (75−100 mg) were switched to FDC BIS + ASA (either 5/75 mg or 10/75 mg) ≥4 weeks prior to study initiation. Adherence was estimated from pill counts and patients' diaries (1−2 months and 3 months after inclusion) and using Morisky's Medication Adherence Scale (MMAS) at 3 months. BP control with the two treatments was compared. A total of 356 patients were enrolled (mean (SD) age: 64.3 ± 11.9 years, 56.5% male). Mean (SD) duration of prior treatment with two-pill BIS and ASA was 17.8 ± 26.6 months. FDC adherence was excellent or good (≥76%) in 98.3% and 98.0% of patients based on pill counts and patients' diaries, respectively. Overall MMAS score was 3.1 ± 1.0. A significant decrease was observed in mean systolic BP, mean diastolic BP and heart rate over the 3-month period (all p < 0.001). FDC BIS + ASA was associated with excellent adherence and improved BP control. The majority (78.7%) of patients preferred the FDC.