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.

Cardiovascular and autonomic responses to whole-body cryostimulation in essential hypertension.

Over recent years, a considerable increase in the popularity of cryostimulation and whole body cryotherapy (WBC) procedures has occurred both among healthy individuals and in various groups of patients, including those with primary untreated hypertension. The aim of this study was to compare the effects of WBC on the functional parameters of cardiovascular system in normotensive and primarily hypertensive individuals. The study included 26 young male volunteers with normal blood pressure range (NormoBP) and 13 with essential arterial hypertension (HyperBP). Each subject was exposed to cryotherapeutic factor (whole-body cryotherapy/cryostimulation, WBC) at a temperature of approximately -115°C to -125°C for a period of 3 min. The cardiovascular and autonomic parameters were measured noninvasively with Task Force® Monitor. Measurements in a supine position and tilt test were performed "before WBC" and "after WBC". Our study revealed that cryogenic temperatures exert strong modulatory effect on the cardiovascular system. Both groups showed adaptive changes of myocardial and vascular parameters in response to rapid cooling of virtually the whole body surface. While the profiles of some of these changes were similar in both the groups, also several considerable intergroup differences were documented. Consequently, the cryostimulation and cryotherapy treatment should be prescribed carefully to individuals who present with cardiovascular failure of any degree.

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.

The influence of elevated heart rate assessed by automated office blood pressure measurement on the risk of cardiovascular events.

INTRODUCTION: The predictive value of heart rate (HR) assessed using an automated office blood pressure measurement (AOBPM) remains unknown. OBJECTIVES: This study aimed to determine the impact of AOBPM HR on the risk of cardiovascular events in hypertensive patients with and without prior cardiovascular disease (CVD). PATIENTS AND METHODS: Data of 9361 participants of the Systolic Blood Pressure Intervention Trial (median follow­up, 3.26 years) were used to perform a post hoc analysis based on baseline AOBPM HR levels (<50, 50-60, 60-70, 70-80, and >80 bpm). Clinical composite end point (CE) was defined as myocardial infarction (MI), acute coronary syndrome other than MI, heart failure exacerbation, stroke, or cardiovascular death. Cardiovascular­related and all­cause mortalities were also evaluated. RESULTS: A total of 1877 participants with and 7484 individuals without CVD were included. Those with higher baseline HR were less frequently men and more often smokers, had higher body mass index and estimated glomerular filtration rate, lower baseline systolic blood pressure, and higher diastolic blood pressure. No differences were observed in the CE frequency, its components, and all­cause death between the baseline HR groups. Elevated HR (>70 bpm) was associated with a higher risk of CE, MI, and cardiovascular death in a multivariable Cox model. Moreover, the model determining the MI risk showed a J­shaped relationship with HR and a significant interaction term (P = 0.049) between HR and CVD history. CONCLUSIONS: High AOBPM HR is associated with a higher risk of cardiovascular events and mortality, whereas low HR may result in higher MI risk in patients with previous CVD.

Cardioprotection Using Strain-Guided Management of Potentially Cardiotoxic Cancer Therapy: 3-Year Results of the SUCCOUR Trial.

BACKGROUND: Global longitudinal strain (GLS) can predict cancer therapeutics-related cardiac dysfunction and guide initiation of cardioprotection (CPT). OBJECTIVES: In this study, the authors sought to determine whether echocardiography GLS-guided CPT provides less cardiac dysfunction in survivors of potentially cardiotoxic chemotherapy, compared with usual care at 3 years. METHODS: In this international multicenter prospective randomized controlled trial, patients were enrolled from 28 international sites. All patients treated with anthracyclines with another risk factor for heart failure were randomly allocated to GLS-guided (>12% relative reduction in GLS) or ejection fraction (EF)-guided (>10% absolute reduction of EF to <55%) CPT. The primary end point was the change in 3-dimensional (3D) EF (ΔEF) from baseline to 3 years. RESULTS: Among 331 patients enrolled, 255 (77%, age 54 ± 12 years, 95% women) completed 3-year follow-up (123 in the EF-guided group and 132 in the GLS-guided group). Most had breast cancer (n = 236; 93%), and anthracycline followed by trastuzumab was the most common chemotherapy regimen (84%). Although 67 (26%) had hypertension and 32 (13%) had diabetes mellitus, left ventricular function was normal at baseline (EF: 59% ± 6%, GLS: 20.7% ± 2.3%). CPT was administered in 18 patients (14.6%) in the EF-guided group and 41 (31%) in the GLS-guided group (P = 0.03). Most patients showed recovery in EF and GLS after chemotherapy; 3-year ΔEF was -0.03% ± 7.9% in the EF-guided group and -0.02% ± 6.5% in the GLS-guided (P = 0.99) group; respective 3-year EFs were 58% ± 6% and 59% ± 5% (P = 0.06). At 3 years, 17 patients (5%) had cancer therapeutics-related cardiac dysfunction (11 in the EF-guided group and 6 in the GLS guided group; P = 0.16); 1 patient in each group was admitted for heart failure. CONCLUSIONS: Among patients taking potentially cardiotoxic chemotherapy for cancer, the 3-year data showed improvement of LV dysfunction compared with 1 year, with no difference in ΔEF between GLS- and EF-guided CPT. (Strain Surveillance of Chemotherapy for Improving Cardiovascular Outcomes [SUCCOUR]; ACTRN12614000341628).

Consistency among Office, Home, and Ambulatory Blood Pressure Values in Women with Chronic Hypertension and History of Eclampsia or Preeclampsia.

Adequate control of blood pressure (BP) is essential to prevent complications in pregnant women with a history of eclampsia or pre-eclampsia. However, the importance of office (OBPM), home (HBPM), and ambulatory (ABPM) BP measurements for proper control and prognosis in high-risk pregnancy is unknown. The present study aimed to compare BP values obtained during these three different BP measurements in women with a history of eclampsia or pre-eclampsia. This study included 79 pregnant women with chronic hypertension and a documented history of eclampsia or pre-eclampsia in previous pregnancy/pregnancies. Every fifth week of the study, all participants underwent ABPM, HBPM and OBPM. BP values from the 10th, 25th, and 37th weeks of pregnancy were evaluated. Therapy was intended to meet the ABPM treatment goal of <130/80 mmHg. Day, night, and 24 h ABPM systolic BP values were lower than HBPM and OBPM values at each study visit. Night and 24 h ABPM diastolic BP values were lower than HBPM and OBPM values, while day 24 h ABPM values were slightly higher than HBPM and OBPM values. ABPM provides different BP values than OBPM and HBPM. Target BP for ABPM in high-risk pregnancy hypertension should be estimated based on the predictive value of adverse pregnancy outcomes.

Answering Clinical Questions Using Machine Learning: Should We Look at Diastolic Blood Pressure When Tailoring Blood Pressure Control?

Background: The guidelines recommend intensive blood pressure control. Randomized trials have focused on the relevance of the systolic blood pressure (SBP) lowering, leaving the safety of the diastolic blood pressure (DBP) reduction unresolved. There are data available which show that low DBP should not stop clinicians from achieving SBP targets; however, registries and analyses of randomized trials present conflicting results. The purpose of the study was to apply machine learning (ML) algorithms to determine, whether DBP is an important risk factor to predict stroke, heart failure (HF), myocardial infarction (MI), and primary outcome in the SPRINT trial database. Methods: ML experiments were performed using decision tree, random forest, k-nearest neighbor, naive Bayesian, multi-layer perceptron, and logistic regression algorithms, including and excluding DBP as the risk factor in an unselected and selected (DBP < 70 mmHg) study population. Results: Including DBP as the risk factor did not change the performance of the machine learning models evaluated using accuracy, AUC, mean, and weighted F-measure, and was not required to make proper predictions of stroke, MI, HF, and primary outcome. Conclusions: Analyses of the SPRINT trial data using ML algorithms imply that DBP should not be treated as an independent risk factor when intensifying blood pressure control.

Cardiotoxicity of the anticancer therapeutic agent bortezomib.

Recent case reports provided alarming signals that treatment with bortezomib might be associated with cardiac events. In all reported cases, patients experiencing cardiac problems were previously or concomitantly treated with other chemotherapeutics including cardiotoxic anthracyclines. Therefore, it is difficult to distinguish which components of the therapeutic regimens contribute to cardiotoxicity. Here, we addressed the influence of bortezomib on cardiac function in rats that were not treated with other drugs. Rats were treated with bortezomib at a dose of 0.2 mg/kg thrice weekly. Echocardiography, histopathology, and electron microscopy were used to evaluate cardiac function and structural changes. Respiration of the rat heart mitochondria was measured polarographically. Cell culture experiments were used to determine the influence of bortezomib on cardiomyocyte survival, contractility, Ca(2+) fluxes, induction of endoplasmic reticulum stress, and autophagy. Our findings indicate that bortezomib treatment leads to left ventricular contractile dysfunction manifested by a significant drop in left ventricle ejection fraction. Dramatic ultrastructural abnormalities of cardiomyocytes, especially within mitochondria, were accompanied by decreased ATP synthesis and decreased cardiomyocyte contractility. Monitoring of cardiac function in bortezomib-treated patients should be implemented to evaluate how frequently cardiotoxicity develops especially in patients with pre-existing cardiac conditions, as well as when using additional cardiotoxic drugs.

Resting Heart Rate and Cardiovascular Outcomes during Intensive and Standard Blood Pressure Reduction: An Analysis from SPRINT Trial.

The association between elevated resting heart rate (RHR) as a cardiovascular risk factor and lowering of systolic blood pressure (SBP) to currently recommended values remain unknown. Systolic Blood Pressure Intervention Trial (SPRINT) data obtained from the NHLBI were used to describe the relationship between RHR and SBP reduction to <120 mmHg compared to SBP reduction to <140 mmHg. The composite clinical endpoint (CE) was defined as myocardial infarction, acute coronary syndrome, decompensation of heart failure, stroke, or cardiovascular death. Increased RHR was associated with a higher CE risk compared with low RHR in both treatment arms. A more potent increase of risk for CE was observed in subjects who were allocated to the SBP < 120 mmHg treatment goal. A similar effect of intensive and standard blood pressure (BP) reduction (p for interaction, 0.826) was observed in subjects with RHR in the 5th quintile (hazard ratio, 0.78, with 95% confidence interval (CI), 0.55-1.11) and in other quintiles of baseline RHR (hazard ratio, 0.75, with 95% CI, 0.62-0.90). Lower in-trial than baseline RHR was associated with reduced CE risk (hazard ratio, 0.80, with 95% CI, 0.66-0.98). We concluded that elevated RHR remains an essential risk factor independent of SBP reduction.

Atrial fibrillation influences automatic oscillometric ankle-brachial index measurement.

INTRODUCTION: Repeated measurements of ankle-brachial index (ABI) using Doppler method were shown to be accurate during atrial fibrillation. Oscillometric devices are effective in ABI measurement, but their accuracy during atrial fibrillation is unknown. The purpose of the study was to investigate whether atrial fibrillation influences ABI obtained with the automatic oscillometric method. MATERIAL AND METHODS: Ninety-nine patients with atrial fibrillation (mean age: 66.6 +(SD = 11) years, M/F - 63/36) who underwent electrical cardioversion were investigated (198 lower extremities). The ABI measurements using oscillometric and Doppler methods were performed on both lower extremities before and after procedure. RESULTS: The ABI measured using the oscillometric method on both lower limbs did not change after cardioversion (1.21 (IQR: 1.13-1.27) vs. 1.22 (IQR: 1.14-1.26), p = 0.664, respectively). The ABI measured before and after cardioversion using Doppler and oscillometric methods showed a significant difference (1.14 (IQR: 1.07-1.22) vs. 1.21 (IQR: 1.13-1.27), p < 0.001 and 1.18 (IQR: 1.09-1.13) vs. 1.22 (IQR: 1.14-1.26), p < 0.001 respectively). Both methods showed a weak correlation before (r = 0.35, p < 0.001) and no correlation after cardioversion (r = 0.12, p = 0.07). The Bland-Altman plot showed poor agreement between measurements performed with the Doppler and oscillometric methods in sinus rhythm and during atrial fibrillation. CONCLUSIONS: The automated oscillometric method of ABI measurements should not replace the reference Doppler method in patients with atrial fibrillation. More research related to the oscillometric measurements is needed in subjects with peripheral artery disease and atrial fibrillation.

Determination of the optimal on-treatment diastolic blood pressure range using automated office measurements in patients without cardiovascular disease.

INTRODUCTION: Optimal diastolic blood pressure (DBP) during antihypertensive treatment in patients without a history of cardiovascular disease (CVD) remains unknown. OBJECTIVES: This post­hoc analysis of the SPRINT (Systolic Blood Pressure Intervention Trial) data aimed to determine the optimal DBP evaluated using automated office blood pressure measurements (AOBPM) in hypertensive patients without a history of CVD. PATIENTS AND METHODS: Data of 1470 patients with CVD and 7117 patients without CVD were used. Clinical composite endpoint (CE) was defined as the occurrence of myocardial infarction, acute coronary syndrome other than myocardial infarction, decompensation of heart failure, stroke, or cardiovascular death. Two different approaches based on the hazard ratio plot were used to identify the optimal DBP range. The first approach was to determine the 10 mm Hg-wide DBP range with the lowest risk for CE. In the second approach, it was assumed that the hazard ratio of CE at the boundary points of the optimal DBP range should be the same in patients with and without CVD. RESULTS: Two ranges of on-treatment DBP were proposed: 73.7 to 83.7 mm Hg (first approach) and 63.6 to 95.8 mm Hg (second approach). The risk for CE was increased by 3% and 20% at the boundary points of the range, respectively, depending on the method of DBP determination. CONCLUSIONS: Due to the fact that the range determined by the second method was wide and substantially different from the one recommended by the European Society of Cardiology (70-79 mm Hg), we have concluded that a DBP range of 73.7 to 83.7 mm Hg, measured using AOBPM, should be considered optimal in patients without CVD.

Cardiac Morphology, Function, and Hemodynamics in Patients With Morbid Obesity and Nonalcoholic Steatohepatitis.

Background The patients with nonalcoholic fatty liver disease demonstrate an increased cardiovascular risk. The adverse influence of liver abnormalities on cardiac function are among many postulated mechanisms behind this association. The aim of the study was to evaluate cardiac morphology and function in patients with morbid obesity referred for bariatric surgery with liver biopsy. Methods and Results We evaluated with echocardiography 171 consecutive patients without known cardiac disease (median age 42 [interquartile range, 37-48] years, median body mass index 43.7 [interquartile range, 41.0-47.5], 67% female patients. Based on the liver biopsy results, there were 44 patients with nonalcoholic steatohepatitis (NASH), 69 patients with isolated steatosis, and 58 patients without steatosis. Patients with NASH demonstrated signs of left ventricular concentric remodeling and hyperdynamic circulation, including indexed left ventricular end-diastolic diameter [cm/m2]: NASH 1.87 [0.22]; isolated steatosis 2.03 [0.33]; without steatosis 2.01 [0.19], P=0.001; relative wall thickness: NASH 0.49±0.05, isolated steatosis 0.47±0.06, without steatosis 0.46±0.06, P=0.011; cardiac index [L/m2]: NASH 3.05±0.54, isolated steatosis 2.80±0.44, without steatosis 2.79±0.50, P=0.013. After adjustment for sex, age, blood pressure, and heart rate, most of the measures of the left ventricular systolic and diastolic function, left atrial size, right ventricular function, and right ventricular size did not differ between groups. Conclusions In a group of patients with extreme obesity, NASH was associated with left ventricular concentric remodeling and hyperdynamic circulation. Increased cardiac output in NASH may represent an additional risk factor for incident cardiovascular events in this population.

Blood pressure profile, sympathetic nervous system activity, and subclinical target organ damage in patients with polycythemia vera.

INTRODUCTION: Polycythemia vera (PV) is a rare myeloproliferative disease associated with an increased prevalence of hypertension and increased risk of cardiovascular complications. However, the precise mechanisms leading to the elevation of blood pressure (BP) and secondary target organ damage remain poorly understood. OBJECTIVES: The study aimed to evaluate BP profile, assess the activity of the sympathetic nervous system and the renin­angiotensin system, and provide a comprehensive assessment of subclinical target organ damage in patients with PV. PATIENTS AND METHODS: Twenty consecutive patients with newly diagnosed PV and 20 control subjects were included. The following were assessed: BP, levels of catecholamines, urinary and plasma O­methylated catecholamine metabolites, concentrations of aldosterone and renin. We also assessed microneurography sympathetic nervous system activity (MSNA) and baroreflex control of heart rate as well as subclinical target organ damage. RESULTS: At similar levels of BP, BP variability was decreased in the PV group (mean [SD] 24­hour systolic BP, 9 [3] vs 12 [3] mm Hg; P = 0.003). Patients with PV had lower norepinephrine excretion (mean [SD], 16.54 [6.32] vs 25.46 [12.88] µg/d; P = 0.03) as well as decreased MSNA as assessed by microneurography compared with controls (mean [SD] MSNA, 30.7 [8.7] bursts/min vs 38.7 [5.4] bursts/min; P = 0.007 and MSNA 51.8 [11] bursts/100 beats vs 61.1 [11.3] bursts/100 heart beats; P = 0.04). Baroreflex control of HR was unaltered in the PV group. Increased hemoglobin levels and red blood cell count correlated with decreased retinal capillary flow in patients with PV. CONCLUSIONS: Patients with PV, characterized by high hemoglobin concentrations and hematocrit levels had lower sympathetic nervous activity and decreased BP variability as compared with controls. There was no relationship between hemoglobin plasma concentration, hematocrit level, and target organ damage.

Cardiovascular risk factors among cancer patients qualified for systemic treatment. Analysis of a cardiovascular disease-free cohort from the Polish multicentre study ONCOECHO.

INTRODUCTION: Cancer therapies are currently more efficient at increasing the survival of patients (pts) with cancer. Unfortunately, the cardiovascular (CV) complications of cancer therapies may adversely affect improving results of treatment. The aim of the study was to evaluate the prevalence of classical CV risk factors among pts with de novo diagnosis of cancer and thus identify the cohort of pts with potentially increased future risk of CV complications. MATERIAL AND METHODS: The analysis is based on the database of the multicentre ONCOECHO study. Pts before systemic treatment (chemotherapy or targeted therapy) were included. The diagnostic datasets of resting electrocardiogram, blood samples, and transthoracic echocardiogram were analysed in 343 consecutive pts who were free from any cardiovascular disease that could adversely affect the introduced treatment. RESULTS: Our cohort included 4.4% of pts with kidney cancer, 7.3% with colorectal cancer, 26.5% with haematological malignancies (HM), and 61.8% with breast cancer. The risk estimated by SCORE was 4.56 ±5.07%. Breast cancer pts had lower cardiovascular risk than those with HM (p = 0.001) and kidney cancer (p = 0.002). Additionally, the HM group had much higher levels of natriuretic peptides (p < 0.001) and creatinine (p = 0.008) than pts with breast cancer. The comparison with the NATPOL population data showed that our pts were more often smokers, hypertensives, and diabetics, but less frequently presented with hypercholesterolaemia. CONCLUSIONS: Patients with new diagnosis of cancer, who are candidates for potentially cardiotoxic medical treatment, have increased prevalence of significant cardiovascular risk factors and therefore should be followed by a multidisciplinary team during the therapeutic process.

Atorvastatin reduces sympathetic activity and increases baroreceptor reflex sensitivity in patients with hypercholesterolaemia and systemic arterial hypertension.

BACKGROUND: Increased sympathetic activity might be related to pathogenesis of hypertension as well as to end organ damage. Animal studies suggest that statins decrease sympathetic activity and increase baroreceptor reflex sensitivity (BRS). AIM: To examine whether atorvastatin decreases muscle sympathetic nerve activity (MSNA) and BRS in hypercholesterolaemic and hypertensive patients. METHODS: Ten patients with essential hypertension and untreated hypercholesterolaemia (aged 43 +/- 12 years) and eight healthy subjects (aged 37 +/- 7 years) were enrolled in the study. In both groups the recordings of microneurography, ECG, blood pressure and BRS were performed twice, before and after 8 weeks during which the patients (but not controls) were treated with atorvastatin. RESULTS: Compared with controls, the patients had higher MSNA values (36.0 +/- 6.6 vs. 29.8 +/- 3.7 bursts/minute), mean BP levels (145.1 +/- 10 vs. 124.1 +/- 11.1 mmHg) and total cholesterol concentration (252.6 +/- 22.6 vs. 179.8 +/- 20.7 mg/dl) baseline values. Statin therapy resulted in a decrease of total cholesterol (252.6 +/- 22.0 vs. 173.8 +/- 26.2 mg/dl, p < 0.05) and MSNA (36.0 +/- 6.6 vs. 28.6 +/- 4.8 bursts/min, p < 0.05), whereas BRS values were increased (12.6 +/- 5.6 vs. 18.1 +/- 5.9 ms/mmHg, p < 0.05). Post-treatment BRS was inversely related to post-treatment MSNA (r = -0.73, p < 0.05). In the controls there were no changes in MSNA (29.8 +/- 3.7 vs. 28.9 +/- 2.9 bursts/min), BRS (11.9 +/- 5.0 vs. 13.1 +/- 4.8 ms/mmHg), total cholesterol, BP and heart rate between the first and the second measurement. CONCLUSION: Atorvastatin reduces MSNA and increases BRS in hypertensive and hypercholesterolaemic patients. Decrease in sympathetic activity may be the result of improvement of baroreceptor function by atorvastatin.

Low on-treatment diastolic blood pressure and cardiovascular outcome: A post-hoc analysis using NHLBI SPRINT Research Materials.

Recent studies including the SPRINT trial have shown beneficial effects of intensive systolic blood pressure reduction over the standard approach. The awareness of the J-curve for diastolic blood pressure (DBP) causes some uncertainty regarding the net clinical effects of blood pressure reduction. The current analysis was performed to investigate effects of low on-treatment DBP on cardiovascular risk in the SPRINT population. The primary composite outcome was the occurrence of myocardial infarction, acute coronary syndrome not resulting in myocardial infarction, stroke, acute decompensated heart failure or death from cardiovascular causes. The prevalence of primary outcomes was significantly higher in subjects within low DBP in both standard (44-67 mmHg [10.8%] vs 67-73 mmHg [6.7%] vs 73-78 mmHg [5.1%] vs 78-83 mmHg [4.4%] vs 83-113 mmHg [4.3%], p < 0.001) and intensive treatment (38-61 mmHg [6.7%] vs 61-66 mmHg [4.1%] vs 66-70 mmHg [4.5%] vs 70-74 mmHg [2.7%] vs 74-113 mmHg [3.4%], p < 0.001) arms. After adjusting for covariates, low DBP showed no significant effects on cardiovascular risk. Therefore, while reaching blood pressure targets, low DBP should not be a matter of concern.

Low Diastolic Blood Pressure is Not Related to Risk of First Episode of Stroke in a High-Risk Population: A Secondary Analysis of SPRINT.

Background Hypertension is the most prevalent and leading risk factor for stroke. SPRINT (The Systolic Blood Pressure Intervention Trial) assessed the effects on cardiovascular event risk of intensive compared with standard systolic blood pressure reduction. In this secondary analysis of SPRINT data, we investigated how low on-treatment diastolic blood pressure ( DBP ) influenced risk for stroke events. Methods and Results For this analysis, we used SPRINT _ POP (Primary Outcome Paper) Research Materials from the National Heart, Lung and Blood Institute (NHLBI) Biologic Specimen and Data Repository Information Coordinating Center. Data for 8944 SPRINT participants were analyzed from the period after target blood pressure was achieved until the end of the trial. Overall, there were 110 stroke events, including 49 from the intensive-treatment arm and 61 in the standard-treatment group. In participants with DBP <70 mm Hg, stroke risk was higher than with DBP ≥70 mm Hg (hazard ratio, 1.467; 95% CI 1.009-2.133; P=0.0445). Univariable Cox proportional hazard risk analysis showed that in the whole group, age and cardiovascular and chronic renal diseases were stroke risk factors. These risk factors were related to lower DBP and higher pulse pressure, however, not to study arm. Multivariable Cox proportional hazard analysis revealed that only age, history of cardiovascular disease, current smoking status and on-treatment systolic blood pressure were significantly related to stroke risk. Conclusions Low on-treatment DBP is not related to the risk for the first stroke, in contrast to older age, the history of cardiovascular disease, current smoking status, and on-treatment systolic blood pressure. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT 01206062.

Determination of optimal on-treatment diastolic blood pressure range using automated measurements in subjects with cardiovascular disease-Analysis of a SPRINT trial subpopulation.

Automated office blood pressure measurement (AOBPM) is recommended for diagnosing hypertension; however, optimal treatment targets using this method are not established. Discrepancies between automated and office measurements of blood pressure have been described, producing uncertainty regarding the use of AOBPM in clinical practice. The Systolic Blood Pressure Intervention Trial (SPRINT) results improved our understanding of target AOBPM systolic blood pressure (SBP) levels; however, diastolic blood pressure (DBP) targets remain unknown. Therefore, we sought to determine the optimal on-treatment DBP range. The analysis was performed on the participants of the SPRINT trial who had hypertension and prior cardiovascular disease. We analyzed the data of 1470 participants (mean age 70.3 ± 9.3 years, 24.1% female) selected from the SPRINT trial database of National Heart, Lung and Blood Institute. The mean achieved SBP and DBP were 127.9 ± 10.7 and 68.3 ± 9.4 mm Hg, respectively. Most of the participants (57.4%) had a DBP lower than 70 mm Hg, while only 11.7% had DPB ≥80 mm Hg. Clinical composite endpoint was defined as myocardial infarction, acute coronary syndrome not resulting in myocardial infarction, stroke, acute decompensated heart failure or death from cardiovascular causes. There were 159 (10.8%) clinical endpoint events. The participants with on-treatment AOBPM DBP range of 68.6-78.6 mm Hg showed the lowest hazard risk of a clinical composite endpoint. These results correspond to the office DBP range of 70-80 mm Hg recommended in ESC guidelines. This is the first attempt to determine the range of optimal DBP values using population-based AOBPM in patients with prior cardiovascular disease.

Statins impair antitumor effects of rituximab by inducing conformational changes of CD20.

BACKGROUND: Rituximab is used in the treatment of CD20+ B cell lymphomas and other B cell lymphoproliferative disorders. Its clinical efficacy might be further improved by combinations with other drugs such as statins that inhibit cholesterol synthesis and show promising antilymphoma effects. The objective of this study was to evaluate the influence of statins on rituximab-induced killing of B cell lymphomas. METHODS AND FINDINGS: Complement-dependent cytotoxicity (CDC) was assessed by MTT and Alamar blue assays as well as trypan blue staining, and antibody-dependent cellular cytotoxicity (ADCC) was assessed by a 51Cr release assay. Statins were found to significantly decrease rituximab-mediated CDC and ADCC of B cell lymphoma cells. Incubation of B cell lymphoma cells with statins decreased CD20 immunostaining in flow cytometry studies but did not affect total cellular levels of CD20 as measured with RT-PCR and Western blotting. Similar effects are exerted by other cholesterol-depleting agents (methyl-beta-cyclodextrin and berberine), but not filipin III, indicating that the presence of plasma membrane cholesterol and not lipid rafts is required for rituximab-mediated CDC. Immunofluorescence microscopy using double staining with monoclonal antibodies (mAbs) directed against a conformational epitope and a linear cytoplasmic epitope revealed that CD20 is present in the plasma membrane in comparable amounts in control and statin-treated cells. Atomic force microscopy and limited proteolysis indicated that statins, through cholesterol depletion, induce conformational changes in CD20 that result in impaired binding of anti-CD20 mAb. An in vivo reduction of cholesterol induced by short-term treatment of five patients with hypercholesterolemia with atorvastatin resulted in reduced anti-CD20 binding to freshly isolated B cells. CONCLUSIONS: Statins were shown to interfere with both detection of CD20 and antilymphoma activity of rituximab. These studies have significant clinical implications, as impaired binding of mAbs to conformational epitopes of CD20 elicited by statins could delay diagnosis, postpone effective treatment, or impair anti-lymphoma activity of rituximab.