Blood pressure variability, nocturnal heart rate variability and endothelial function predict recurrent cerebro-cardiovascular events following ischemic stroke.

Introduction: Cardiovascular parameters characterizing blood pressure (BP), heart rate (HR), endothelial function and arterial stiffness predict cerebro-cardiovascular events (CCVE) in the general population. Considering the paucity of data in stroke patients, we assessed these parameters as potential predictors of recurrent CCVE at acute stroke stroke. Patients and methods: This is a secondary outcome analysis of a prospective observational longitudinal Sleep Deficiency & Stroke Outcome Study (ClinicalTrials.gov Identifier: NCT02559739). The study consecutively recruited acute ischemic stroke patients. Cardiovascular parameters (blood pressure variability [BPV], heart rate variability [HRV], endothelial function, and arterial stiffness) were assessed within the first week post-stroke. Future CCVE were recorded over a 3-year follow-up. Multivariate Cox regression analysis was used to investigate the prognostic value of 48 cardiovascular parameters regarding CCVE risk. Results: Out of 447 recruited patients, 359 were included in this analysis. 20% of patients developed a future CCVE. A high variability of systolic BP (n = 333) and nocturnal HR (non-linear parameters; n = 187) at acute stroke predicted CCVE risk after adjustment for demographic parameters, cardiovascular risk factors and mean BP or HR, respectively. Endothelial dysfunction (n = 105) at acute stroke predicted CCVE risk after adjustment for age and sex, but not after adjustment for cardiovascular risk factors. Diurnal HR and arterial stiffness at acute stroke were not associated with CCVE risk. Conclusion: High blood pressure variability, high nocturnal HRV and endothelial function contribute to the risk for future CCVE after stroke.

Cardiovascular remodeling in active and controlled acromegaly: association with sleep-disordered breathing.

PURPOSE: We hypothesized that an unfavorable cardiovascular profile in acromegaly is associated with sleep-disordered breathing (SDB), while acromegaly control improves both respiratory sleep characteristics and the cardiovascular profile. METHODS: The patients underwent the assessment of breathing during sleep and cardiovascular profile assessment at the start of the study including arterial stiffness, blood pressure, echocardiography, nocturnal heart rate variability (HRV). The assessment was repeated in patients with acromegaly at 1 year after transsphenoidal adenectomy (TSA). RESULTS: A total of 47 patients with acromegaly and 55 control subjects were enrolled. At one year after TSA, 22 patients with acromegaly were reassessed. Multiple linear regression analysis with adjustment for age, sex and body mass index (BMI) showed the associations of insulin growth-like factor 1 (IGF-1) with obstructive apnea index (OAI: ß=0.035/h, p<0.001), but not with cardiovascular parameters, in patients with acromegaly. The analysis of combined acromegaly and control dataset with adjustment for age, sex and BMI showed the association the presence of acromegaly with diastolic blood pressure (DBP; ß=17.99 mmHg, p<0.001), ejection fraction (EF; ß=6.23%, p=0.009), left heart remodeling (left ventricle posterior wall: ß=0.81 mm, p=0.045) and the association of the presence of SDB (apnea-hypopnea index≥15/h) with left ventricular function (EF: -4.12%, p=0.040; end systolic volume: 10.12 ml, p=0.004). Control of acromegaly was accompanied by the decrease in OAI (5.9 [0.8, 14.5]/h and 1.7 [0.2, 5.1]/h, p=0.004) and nocturnal heart rate (66.1 [59.2, 69.8] bpm and 61.7 [54.0, 67.2] bpm, p=0.025) and by the increase in blood pressure (DBP: 78.0 [70.3, 86.0] mm Hg and 80.0 [80.0, 90.0] mm Hg, p=0.012). CONCLUSION: The comorbidities of acromegaly, including sleep-disordered breathing, appear to have a long-term effect on cardiovascular remodeling in active acromegaly. Future studies should investigate the applicability of the treatment of SDB for the reduction of cardiovascular risk in acromegaly.

Pulse wave velocity is decreased in acromegaly compared to non-acromegaly study participants with similar cardiovascular risk profile.

OBJECTIVE: Acromegaly patients were reported to have an increased arterial stiffness that could contribute to the frequent cardiovascular complications in this population. The chronic excess of GH and IGF-1 may lead to arterial stiffening via different mechanisms, including hypertension, impaired glucose tolerance and dyslipidemia, however, it is not known whether the activation of GH/IGF-1 axis might influence arterial stiffening independently of cardiovascular risk factors. The objective of this prospective case-control study was to compare arterial stiffness assessed with pulse-wave velocity (PWV) in acromegaly versus non-acromegaly group with similar cardiovascular risk profile. DESIGN: This prospective case-control study included 27 patients with active acromegaly, who underwent the assessment of clinical, physiological, biochemical parameters and the evaluation of PWV with applanation tonometry. We used "The epidemiology of cardiovascular disease in different regions of the Russian Federation" study database (n = 522) to establish a non-acromegaly control group with similar cardiovascular risk profile (n = 54). Non-acromegaly control participants underwent the same assessment as acromegaly patients except for the measurement of serum GH and IGF-1 levels. We compared PWV in acromegaly patients to the general non-acromegaly cohort and its subset, matched with acromegaly patients for cardiovascular risk factors. We also investigated the associations of PWV with clinical, physiological and biochemical parameters in acromegaly and non-acromegaly group using correlation and regression analysis with adjustment for age and sex. RESULTS: Acromegaly patients had lower PWV (6.70 (5.75-7.65) m/s) compared to unmatched non-acromegaly control cohort (7.50 (6.70-8.57) m/s, p = 0.01) and to the non-acromegaly control group matched for cardiovascular risk factors (7.45 (6.73-8.60), p < 0.01). In non-acromegaly control group PWV was associated with BMI (ρ = 0.40, p < 0.01; ß = 0.09, p < 0.01), obesity (r = 0.46, p < 0.01; ß = 1.36, p < 0.01), systolic blood pressure (ρ = 0.60, p < 0.01; ß = 0.05, p < 0.01), diastolic blood pressure (ρ = 0.62, p < 0.01; ß = 0.07, p < 0.01), triglycerides (ρ = 0.55, p < 0.01; ß = 0.58, p = 0.04), glucose (ρ = 0.54, p < 0.01; ß = 0.70, p < 0.01) and diabetes (r = 0.40, p < 0.01; ß = 1.10, p = 0.03), while in acromegaly group PWV was associated with IGF-1 expressed in mcg/ml (ρ = -0.49, p ≤0.01; ß = -0.002, p ≤0.01) and in percentage of the upper limit of the normal (ρ = -0.47, p = 0.01; ß = -0.005, p ≤0.01) as well as with diuretics treatment (ß = -1.17, p = 0.03). CONCLUSIONS: PWV is decreased in acromegaly patients compared to non-acromegaly control participants with similar cardiovascular risk profile. Future studies need to explore the role of GH/IGF-1 axis in the regulation of arterial wall properties and the reliability of PWV as a prognostic marker of cardiovascular complications in acromegaly.

Caveolin-1 Regulates Perivascular Aquaporin-4 Expression After Cerebral Ischemia.

Edema is a hallmark of many brain disorders including stroke. During vasogenic edema, blood-brain barrier (BBB) permeability increases, contributing to the entry of plasma proteins followed by water. Caveolae and caveolin-1 (Cav-1) are involved in these BBB permeability changes. The expression of the aquaporin-4 (AQP4) water channel relates to brain swelling, however, its regulation is poorly understood. Here we tested whether Cav-1 regulates AQP4 expression in the perivascular region after brain ischemia in mice. We showed that Cav-1 knockout mice had enhanced hemispheric swelling and decreased perivascular AQP4 expression in perilesional and contralateral cortical regions compared to wild-type. Glial fibrillary acidic protein-positive astrocytes displayed less branching and ramification in Cav-1 knockout mice compared to wild-type animals. There was a positive correlation between the area of perivascular AQP4-immunolabelling and branch length of Glial fibrillary acidic protein-positive astrocytes in wild-type mice, not seen in Cav-1 knockout mice. In summary, we show for the first time that loss of Cav-1 results in decreased AQP4 expression and impaired perivascular AQP4 covering after cerebral ischemia associated with altered reactive astrocyte morphology and enhanced brain swelling. Therapeutic approaches targeting Cav-1 may provide new opportunities for improving stroke outcome. SIGNIFICANCE STATEMENT: Severe brain edema worsens outcome in stroke patients. Available treatments for stroke-related edema are not efficient and molecular and cellular mechanisms are poorly understood. Cellular water channels, aquaporins (AQPs), are mainly expressed in astrocytes in the brain and play a key role in water movements and cerebral edema, while endothelial caveolins have been suggested to play a role in vasogenic edema. Here we used an integrative approach to study possible interaction between AQP4 and caveolin-1 (Cav-1) after stroke. Absence of Cav-1 was associated with perivascular changes in AQP4 expression and enhanced brain swelling at 3 days after cerebral ischemia. The present work indicates a direct or indirect effect of Cav-1 on perivascular AQP4, which may lead to novel edema therapy.

Neuroprotective effect of glucagon-like peptide-1 receptor agonist is independent of glycaemia normalization in type two diabetic rats.

OBJECTIVE: Stroke is a severe complication of type 2 diabetes mellitus. Glucagon-like peptide-1 receptor agonists have been shown to have a neuroprotective effect in experimental diabetes. The aim of this study was to determine if their neuroprotective effect is an independent property of the drug independent of glycaemic control. METHODS: This two-phase study used male Wistar rats. In the first phase, experimental animals were pretreated with liraglutide, while controls received only vehicle. After transient focal brain ischaemia modelling, neurological deficit and brain infarct volume were measured. In the second phase, the first and the second groups of experimental animals with type 2 diabetes mellitus received liraglutide and metformin, respectively, while control animals with diabetes received only vehicle. After transient focal brain ischaemia modelling, neurological deficit and brain infarct volume were evaluated. RESULTS: Pretreatment with liraglutide in diabetic and non-diabetic animals reduced infarct size as compared to controls, while only non-diabetic liraglutide-treated rats presented neurologic deficit decreases. Despite glycaemia normalization, metformin-treated diabetic rats had no differences in stroke outcome when compared to the control group. CONCLUSION: The neuroprotective effect of liraglutide is not associated with glycaemic control amelioration in experimental type 2 diabetes mellitus.